A novel double mutation of SASH1 associated with Generalized Lentiginosis and unilateral renal dysplasia: pedigree survey and literature review

A novel double mutation of SASH1 associated with Generalized Lentiginosis and unilateral renal dysplasia: pedigree survey and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A novel double mutation of SASH1 associated with Generalized Lentiginosis and unilateral renal dysplasia: pedigree survey and literature review Jiang Du, Guobiao Liang, Tao Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4393712/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A 19-year-old female patient, diagnosed with generalized lentiginosis and the right renal dysplasia, had all other systems found to be normal. Whole exome sequencing identified double heterozygous missense mutations, c.1029C > T and c.1566C > A, in the SASH1 gene. Her parents each carry a single-site mutation, c.1029C > T, and do not exhibit the similar lentiginous phenotype. According to the literature, both mutation sites are unprecedented, with the c.1566C > A variation representing a novel occurrence within this lineage. The primary pathogenic mutation was identified at c.1566C > A, while the evidence for the pathogenicity of c.1029C > T remains insufficient. There are currently no reported cases in the literature where this gene mutation has led to such symptoms. This finding not only contributes to the expansion of the human gene mutation repository but also provides crucial insights for the genetic counseling of the patient and her relatives. During these consultations, it is essential to elucidate the characteristics and implications of these mutations to accurately gauge the patient's risk factors and inform future familial health decisions. SASH1 gene mutation generalized lentiginosis unilateral renal dysplasia Figures Figure 1 Figure 2 Introduction Generalized lentiginosis (GL) is a rare pigmentary disorder characterized by multiple hyperpigmented macules distributed over the body. Some patients may also present with extracutaneous systemic diseases. Recent research has identified the SASH1 (SAM and SH3 domain-containing protein 1) gene as a culprit gene for GL [ 1 ] . However, no literature supports the association between this gene mutation and renal dysplasia [ 2 ] , nor have any cases of GL combined with unilateral renal dysplasia been reported. This study has recently treated one patient clinically diagnosed with GL combined with unilateral renal dysplasia. To clarify the diagnosis and provide genetic counseling, we conducted full exome sequencing and reviewed relevant literature to perform gene testing and genetic analysis on this patient. Medical history A 19-year-old female patient has been suffering from generalized hyperpigmentation for over a decade. Upon recent physical examination, right kidney dysplasia was noted. She had a history of multiple visits to dermatology clinics at other hospitals, where she had previously been diagnosed with GL. Her parents are healthy and report no consanguinity; moreover, there are no other family members with similar phenotypic features. On physical examination, she was found to be intellectually normal with good growth and development. She had scattered macules of varying shades of brown on her skin, predominantly in sun-exposed areas. These lesions became darker with sun exposure and then faded again, with some fading with age and not involving the oral mucosa (Fig. 1 ). No other systemic abnormalities were detected during the examination. Auxiliary examinations included an abdominal CT scan with plain and enhanced imaging that showed "right renal dysplasia with compensatory hypertrophy of the left kidney." Renal ECT demonstrated absence of function in the right kidney and preserved function in the left kidney." The electrocardiogram exhibited T-wave abnormalities. The list of normal auxiliary examination results ("Echocardiography revealed normal cardiac structure, blood flow, and left ventricular systolic function, with a normal chest X-ray. ") On October 28, 2023, the patient underwent a "laparoscopic right nephrectomy," and the postoperative pathology confirmed chronic pyelonephritis of the right kidney and chronic inflammation of the ureteral mucosa. Recovery was uneventful, and the patient was discharged from the hospital. Genetic testing was performed on the patient and her parents using peripheral blood samples. Whole-exome sequencing was conducted by BGI Genomics. Genetic testing revealed two heterozygous missense variants in the SASH1 gene, c.1029C > T (p.Thr343=) and c.1566C > A (p.Ser522Arg). Sanger sequencing was used to confirm the identified variants, and genetic analysis of the parents confirmed they each carried one copy of the SASH1 c.1029C > T (p.Thr343=) variant (as shown in Fig. 2 ). Discussion SASH1 is a SLY gene family member encoding scaffold proteins widely expressed in human tissues. It plays diverse biological roles, including an anti-cancer role in various cancers [ 3 ] . With the continuous improvement of genetic testing technology, PTPN11, BRAF, RAF1, and SASH1 gene mutations have been found to be closely associated with Generalized Lentiginosis (GL) in recent years [ 4 ] . Although SASH1 mutations have been detected in multiple cases of GL [ 5 ] , they account for a very small proportion of the total case count. Recent studies have confirmed that SASH1 mutations can inhibit TGF-β1 signaling pathway, leading to abnormal morphology and positioning of melanocytes in the epidermal cells, thereby causing abnormal pigment deposition [ 6 ] . This finding may provide initial insights into the pathogenic mechanisms of skin abnormal pigmentation caused by mutations in the SASH1 gene. GL is a rare autosomal dominant skin genetic disease. The clinical presentation primarily manifests in infants with a widespread distribution of dark brown to black pigmented lesions across the body, particularly in sun-exposed areas, and can affect mucosal surfaces such as those inside the mouth and around the genitals. According to whether there are systemic damages outside the skin, it can be divided into GL and Leopard syndrome (LS). LS could affect various other organ systems, including the cardiovascular, respiratory, nervous, skeletal, and urinary reproductive systems [ 7 ] . There have been rare reports of LS combined with unilateral kidney dysplasia (no gene mutation detected) or renal malformations (PTPN11 gene mutation) cases [ 8 ] . However, the diagnosis of LS requires at least two non-skin lesions [ 9 ] . In this case, the patient only with unilateral kidney dysplasia, which did not reach the diagnostic criteria for LS. GL needs to be differentiated from dyschromatosis universalis hereditaria (DUH). DUH is characterized by a pattern of hyperpigmented and hypopigmented macules intermixed with each other. The skin lesions are associated with systemic involvement that is unrelated to sun exposure, and they do not change with age or season. In this case, the first affected individual has hyperpigmentation spots mainly distributed in exposed areas, with no pigment depigmentation spots throughout the body. And with age, the hyperpigmentation spots had decreased [ 10 ] . Therefore, considering the results of gene detection, it was considered that this patient has GL. SASH1 gene is also one of the main pathogenic genes of DUH [ 11 ] . This overlap of clinical syndromes with other genes is called genetic heterogeneity. The phenotype depends on the gene mutation site; new mutations in the SASH1 gene may lead to concomitant occurrence of GL and renal developmental abnormalities, which may also be coincidental. During physical examination after adulthood, the right kidney of this patient was found to have developmental abnormalities and no function by chance. Combined with preoperative CT and intraoperative conditions, it met the diagnosis of renal dysplasia (Fig. 1 ). The diseased kidney had no value for retention, so it has been removed to avoid the occurrence of corresponding complications. According to the whole exome sequencing results, the patient had presented with double heterozygous missense mutations in the SASH1 gene, specifically c.1029C > T and c.1566C > A, which had not been reported elsewhere. Her parents each carried a heterozygous missense variant in the SASH1 gene at c.1029C > T, suggesting that the patient inherited this mutation from them. However, c.1566C > A represents a novel mutation. Protein function prediction software, such as REVEL, suggested that the c.1029C > T site mutation was relatively benign, whereas the c.1566C > A site mutation had a higher probability of being pathogenic. Further analysis based on family history revealed that the c.1029C > T variant is a synonymous mutation located outside the functional domain of the SASH1 gene and distant from the exon boundaries, thus having minimal impact on gene splicing. Moreover, none of the patient's parents or other relatives exhibited phenotypic manifestations, indicating that this site lacks sufficient evidence for being pathogenic. Given the insufficient evidence of pathogenicity for the c.1029C > T mutation and the presence of typical clinical manifestations of GL in the patient, combined with the novelty and potentially pathogenic nature of the c.1566C > A mutation, which is likely to be inherited in a dominant manner, it is concluded that the c.1566C > A mutation carries a higher risk of being transmitted to offspring. To date, only 20 cases of GL (male: female = 15: 8, age range 2–40, sporadic: familial = 9:13) have been identified to be associated with mutations in the SASH1 gene, with a total of 18 pathogenic mutation sites identified (contains the type of gene mutation: Missense, Frameshift and Duplication) (as shown in Table 1 ). Some research statistics indicate that the SLY domain contains more than 70% of the SASH1 variants related to pigmentary disorders [ 12 ] . In this study, most SASH1 gene mutation sites are distributed within the SLY domain [ 13 ] . For instance, the pathogenic mutation site in this patient is located in exon 14 (part of the SLY domain), while non-pathogenic mutations are found in exon 10 (non-functional region); further analysis suggests that mutations leading to functional abnormalities in the SLY domain may be closely linked to the development of GL. Compared to other cases, this case is unique for having dual mutations in the SASH1 gene; one of these new mutations was identified in the family. Non-pathogenic mutations inherited from parents might influence the stability of the SASH1 gene. These mutations could lead to new mutations under genetic, lifestyle, or environmental changes. The age range of patients with GL is quite broad, reaching up to 40 years old without any other systemic damage. The onset of this disease may occur early in life, but systemic lesions often manifest later in adulthood or even later. The specific age at which these changes occur remains uncertain, necessitating lifelong follow-up monitoring. In summary, this study identifies for the first time a novel double mutation in the SASH1 gene from a sporadic case of GL using whole exome sequencing technology. Through family investigation, researchers determined the pathogenic mutation (c.1566C > A) while excluding the non-pathogenic mutation (c.1029C > T). This marks the first report of the novel pathogenic mutation SASH1 (c.1566C > A), which may cause both GL and unilateral renal hypoplasia. This discovery not only enriches the human gene mutation database but also provides valuable information for genetic counseling of affected individuals. Currently, there is no specific treatment for GL; thus, early diagnosis, comprehensive health assessments, and early interventions for extracutaneous systemic damage are critical to improving prognosis. It is recommended to establish long-term management and follow-up protocols to control existing symptoms and prevent future health issues. Table 1 Statistics on GL cases related to mutations in the SASH1 gene. Patient Author/Years Ethnicity Gender Age at diagnosis (Age at onset) Inheritance(Family member with the same mutation) Variant Variant type Other system damage 1 Shellman et al [ 1 ] .(2015) Spanish Male / Familial c.1556G > A (p.Ser519Asn) Missense NO 2–3 Zhang J et al [ 4 ] .(2016) Chinese Male 15 years(after birth) Sporadic c.1527_1530dupAAGT (p.Leu511Lysfs*21) Frameshift NO Male 7 years(3 years) Familial c.1537A > C (p.Ser513Arg) Missense 4–5 Wang Jianbo et al [ 5 ] .(2016) Chinese Male 27 years(18 months) Familial(mother) c.1519T > G (p.Ser507Ala) Missense NO 6–8 Zhang Tianjiao et al [ 14 ] .(2020) Chinese Male 9 years(3 months) Sporadic c.1526_1527insAAGT (p.Leu511Lysfs*21) Frameshift Male 8 years(6 months ) c.1520C > T (p.Ser507Phe) Missense NO Female 6 years(6 months) c.1761C > G (p.Ser587Arg) 9–14 Yuta Araki et al [ 15 ] .(2021) Japanese Male 3 years(14 months) Sporadic c.1758C > G (p.Iie586Met) Missense NO Female 27 years(2 years) Familial c.1592C > A (p.Ser531Yyr) Female 4 years(2 years) Sporadic c.1574C > G (p.Thr525Arg) Male 3 years(8 months) Sporadic c.1547G > T (p.Ser516IIe) Female 16 years(3 years) Familial(father) c.1930C > T (p.Arg644Trp) 15–16 Li Bo et al [ 16 ] .(2022) Chinese Male 12 years(4 years) Familial(father) c.49_54dupCCCGAG (p. P17_E18dup) Duplication NO 17–19 Jae Yeon Kim et al [ 17 ] .(2023) Korean Male 2 years(8 months) Familial(father) c.1528A > T (p.Ser510Cys) Missense NO Male 6 years(after birth) Sporadic c.1574C > T (p.Thr525IIe) 20–21 Kexin Guo et al [ 13 ] .(2023) Chinese Female 12 years(after birth) Sporadic c.1548T > A (p.Ser516Arg) Missense NO Male 40 years(after birth) Sporadic c.1811C > A (p.Thr604Lys) 22 This study Chinese Female 19 years(after birth) Sporadic c.1029C > T(p.Thr343=) and c.1566C > A(p.Ser522Arg) Missense Unilateral renal dysplasia Declarations Ethics approval and consent to participate This study was approved by Ethics Committee of Affiliated Hospital of Zunyi Medical University. Consent for publication Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Author contributions Jiang Du Collect clinical data and wrote the papers. Guobiao Liang and Tao Wu Guided the treatment and reviewed manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. References SHELLMAN Y G, LAMBERT K A, BRAUWEILER A, et al. SASH1 Is Involved in an Autosomal Dominant Lentiginous Phenotype[J]. The Journal of investigative dermatology, 2015, 135(12): 3192-4. SANNA-CHERCHI S, WESTLAND R, GHIGGERI G M, et al. Genetic basis of human congenital anomalies of the kidney and urinary tract[J]. The Journal of clinical investigation, 2018, 128(1): 4-15. BURGESS J T, BOLDERSON E, ADAMS M N, et al. SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer[J]. Scientific reports, 2020, 10(1): 18605. ZHANG J, CHENG R, LIANG J, et al. Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination[J]. Clinical genetics, 2016, 90(4): 372-7. WANG J, ZHANG J, LI X, et al. A Novel De novo Mutation of the SASH1 Gene in a Chinese Family with Multiple Lentigines[J]. Acta dermato-venereologica, 2017, 97(4): 530-1. CUI H, GUO S, HE H, et al. SASH1 promotes melanin synthesis and migration via suppression of TGF-β1 secretion in melanocytes resulting in pathologic hyperpigmentation[J]. International journal of biological sciences, 2020, 16(7): 1264-73. VELAYUTHAM R, AHMED A S. LEOPARD syndrome with hypertrophic cardiomyopathy [J]. QJM : monthly journal of the Association of Physicians, 2023, 116(5): 375-6. CHEN Yusha, ZOU Meirong, SONG Deyu, et al. A Case of LEOPAＲD Syndrome Caused by PTPN11 Gene Mutation[J].Chin J Dermatovenereol. 2021, 35(08): 904-7. DIGILIO M C, SARKOZY A, DE ZORZI A, et al. LEOPARD syndrome: clinical diagnosis in the first year of life[J]. American journal of medical genetics Part A, 2006, 140(7): 740-6. ZHANG J, LI M, YAO Z. Updated review of genetic reticulate pigmentary disorders[J]. The British journal of dermatology, 2017, 177(4): 945-59. MURTHY A B, PALANIAPPAN V, KARTHIKEYAN K, et al. Dyschromatosis universalis hereditaria[J]. International journal of dermatology, 2023, 62(10): 1218-27. CLEMENTS C M, VöGELI B, SHELLMAN Y G, et al. Solution NMR backbone assignment of the SASH1 SLy proteins associated disordered region (SPIDER) [J]. Biomolecular NMR assignments, 2023, 17(1): 151-7. GUO K, LIU J W, ZHANG R, et al. Genetic and phenotypic heterogeneity of multiple lentigines and precise diagnosis in four Chinese families with multiple lentigines [J]. Pigment cell & melanoma research, 2023, 36(3-4): 288-98. ZHANG Tian-jiao, YANG Xiu-min, WEI Ai-hua. Study on SASH1 genetic mutations in 3 patients of generalized lentiginosis[J]. Journal of Practical Dermatology. 2020, 13(06): 333-6. ARAKI Y, OKAMURA K, SAITO T, et al. Five novel mutations in SASH1 contribute to lentiginous phenotypes in Japanese families [J]. Pigment cell & melanoma research, 2021, 34(2): 174-8. Li Bo, Wen Guangdong, Yu Cong, et al. Gene mutation analysis of a family with familial generalized lentiginosis. Chinese Journal of Dermatology [J]. 2022, 55(2): 146-9. KIM J Y, KWON I J, LEE S E. Two novel mutations in SASH1 identified in a familial and a sporadic generalized lentiginosis phenotype in Koreans [J]. Clinical and experimental dermatology, 2023, 48(10): 1171-3. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4393712","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":302147713,"identity":"643ba300-32ae-4b5e-8fd1-bce642e81d2d","order_by":0,"name":"Jiang Du","email":"","orcid":"","institution":"Affiliated Hospital of Zunyi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Jiang","middleName":"","lastName":"Du","suffix":""},{"id":302147714,"identity":"aa86bfc3-a37a-4e4a-bc4f-ff49ac4effe6","order_by":1,"name":"Guobiao Liang","email":"","orcid":"","institution":"Affiliated Hospital of Zunyi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Guobiao","middleName":"","lastName":"Liang","suffix":""},{"id":302147715,"identity":"ce4d5583-e953-4844-bd79-5eb641e23bad","order_by":2,"name":"Tao Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYLCCBAYJOTZm5gMHPvwgTgNjQwKDjTE/e1viwZk9xGphYEhLlOw5Y3yYg40I9brtZ58/eLjjcILBjZwPhxl4GOT5xQ7g12J2Jt2wIfHM4TyDG7kbDhdYMBjOnJ1AQMuBNMaGxLbDxWAtM3gYEgxuE9Jy/hlYS+KGGzkPDvOwEaPlBtiWtMSZPWcYiNXyjHFGYhs4kA2AgSxBhF/OpzF8/NkGjsrHHz78sJHnlyagBR1IkKZ8FIyCUTAKRgF2AAAOxUy65ogoTQAAAABJRU5ErkJggg==","orcid":"","institution":"Affiliated Hospital of Zunyi Medical College","correspondingAuthor":true,"prefix":"","firstName":"Tao","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2024-05-09 08:26:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4393712/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4393712/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57036279,"identity":"e8b3f394-915b-4ad5-981f-9b0b7fea6a40","added_by":"auto","created_at":"2024-05-23 18:38:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":19377316,"visible":true,"origin":"","legend":"\u003cp\u003eThe images labeled A and B depict patches of light and dark brown pigmentation across the patient's body, characterized by well-defined boundaries and symmetrical patterns, with more pronounced lesions occurring in sun-exposed areas. In images C and D, preoperative CT scanned reveal abnormal development of the right kidney, displayed reduced volume, an irregular shape, and a multilocular cystic structure. Additionally, the left kidney appeared compensatorily enlarged. Postoperative images E and F revealed the affected kidney to have significantly reduced size, thin cortex, and cystic transformation. Evidence of narrowed and obstructed ureteral development, as indicated by the yellow box marker, was consistent with features of renal dysplasia.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4393712/v1/8ecca2c794674c66faa6daf5.png"},{"id":57036277,"identity":"71c3d57c-6f4b-4422-a2ba-f68df8f35952","added_by":"auto","created_at":"2024-05-23 18:38:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":678359,"visible":true,"origin":"","legend":"\u003cp\u003eThe Sanger sequencing validation results of the SASH1 gene in the proband's family.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4393712/v1/79d887b9739678a3bc497596.png"},{"id":58661241,"identity":"2a649faa-6f92-47a0-aaee-a3f54ef6dd2e","added_by":"auto","created_at":"2024-06-19 12:35:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":28801794,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4393712/v1/a2e9c9ba-2e28-4bc3-b73f-a45c78b4b35d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A novel double mutation of SASH1 associated with Generalized Lentiginosis and unilateral renal dysplasia: pedigree survey and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGeneralized lentiginosis (GL) is a rare pigmentary disorder characterized by multiple hyperpigmented macules distributed over the body. Some patients may also present with extracutaneous systemic diseases. Recent research has identified the SASH1 (SAM and SH3 domain-containing protein 1) gene as a culprit gene for GL\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. However, no literature supports the association between this gene mutation and renal dysplasia\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, nor have any cases of GL combined with unilateral renal dysplasia been reported. This study has recently treated one patient clinically diagnosed with GL combined with unilateral renal dysplasia. To clarify the diagnosis and provide genetic counseling, we conducted full exome sequencing and reviewed relevant literature to perform gene testing and genetic analysis on this patient.\u003c/p\u003e"},{"header":"Medical history","content":"\u003cp\u003eA 19-year-old female patient has been suffering from generalized hyperpigmentation for over a decade. Upon recent physical examination, right kidney dysplasia was noted. She had a history of multiple visits to dermatology clinics at other hospitals, where she had previously been diagnosed with GL. Her parents are healthy and report no consanguinity; moreover, there are no other family members with similar phenotypic features. On physical examination, she was found to be intellectually normal with good growth and development. She had scattered macules of varying shades of brown on her skin, predominantly in sun-exposed areas. These lesions became darker with sun exposure and then faded again, with some fading with age and not involving the oral mucosa (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). No other systemic abnormalities were detected during the examination. Auxiliary examinations included an abdominal CT scan with plain and enhanced imaging that showed \"right renal dysplasia with compensatory hypertrophy of the left kidney.\" Renal ECT demonstrated absence of function in the right kidney and preserved function in the left kidney.\" The electrocardiogram exhibited T-wave abnormalities. The list of normal auxiliary examination results (\"Echocardiography revealed normal cardiac structure, blood flow, and left ventricular systolic function, with a normal chest X-ray. \") On October 28, 2023, the patient underwent a \"laparoscopic right nephrectomy,\" and the postoperative pathology confirmed chronic pyelonephritis of the right kidney and chronic inflammation of the ureteral mucosa. Recovery was uneventful, and the patient was discharged from the hospital. Genetic testing was performed on the patient and her parents using peripheral blood samples. Whole-exome sequencing was conducted by BGI Genomics. Genetic testing revealed two heterozygous missense variants in the SASH1 gene, c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Thr343=) and c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Ser522Arg). Sanger sequencing was used to confirm the identified variants, and genetic analysis of the parents confirmed they each carried one copy of the SASH1 c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Thr343=) variant (as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSASH1 is a SLY gene family member encoding scaffold proteins widely expressed in human tissues. It plays diverse biological roles, including an anti-cancer role in various cancers\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. With the continuous improvement of genetic testing technology, PTPN11, BRAF, RAF1, and SASH1 gene mutations have been found to be closely associated with Generalized Lentiginosis (GL) in recent years\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Although SASH1 mutations have been detected in multiple cases of GL\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, they account for a very small proportion of the total case count. Recent studies have confirmed that SASH1 mutations can inhibit TGF-β1 signaling pathway, leading to abnormal morphology and positioning of melanocytes in the epidermal cells, thereby causing abnormal pigment deposition\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. This finding may provide initial insights into the pathogenic mechanisms of skin abnormal pigmentation caused by mutations in the SASH1 gene.\u003c/p\u003e \u003cp\u003eGL is a rare autosomal dominant skin genetic disease. The clinical presentation primarily manifests in infants with a widespread distribution of dark brown to black pigmented lesions across the body, particularly in sun-exposed areas, and can affect mucosal surfaces such as those inside the mouth and around the genitals. According to whether there are systemic damages outside the skin, it can be divided into GL and Leopard syndrome (LS). LS could affect various other organ systems, including the cardiovascular, respiratory, nervous, skeletal, and urinary reproductive systems\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. There have been rare reports of LS combined with unilateral kidney dysplasia (no gene mutation detected) or renal malformations (PTPN11 gene mutation) cases\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. However, the diagnosis of LS requires at least two non-skin lesions\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. In this case, the patient only with unilateral kidney dysplasia, which did not reach the diagnostic criteria for LS.\u003c/p\u003e \u003cp\u003eGL needs to be differentiated from dyschromatosis universalis hereditaria (DUH). DUH is characterized by a pattern of hyperpigmented and hypopigmented macules intermixed with each other. The skin lesions are associated with systemic involvement that is unrelated to sun exposure, and they do not change with age or season. In this case, the first affected individual has hyperpigmentation spots mainly distributed in exposed areas, with no pigment depigmentation spots throughout the body. And with age, the hyperpigmentation spots had decreased\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Therefore, considering the results of gene detection, it was considered that this patient has GL. SASH1 gene is also one of the main pathogenic genes of DUH\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. This overlap of clinical syndromes with other genes is called genetic heterogeneity. The phenotype depends on the gene mutation site; new mutations in the SASH1 gene may lead to concomitant occurrence of GL and renal developmental abnormalities, which may also be coincidental. During physical examination after adulthood, the right kidney of this patient was found to have developmental abnormalities and no function by chance. Combined with preoperative CT and intraoperative conditions, it met the diagnosis of renal dysplasia (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The diseased kidney had no value for retention, so it has been removed to avoid the occurrence of corresponding complications.\u003c/p\u003e \u003cp\u003eAccording to the whole exome sequencing results, the patient had presented with double heterozygous missense mutations in the SASH1 gene, specifically c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T and c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A, which had not been reported elsewhere. Her parents each carried a heterozygous missense variant in the SASH1 gene at c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T, suggesting that the patient inherited this mutation from them. However, c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A represents a novel mutation. Protein function prediction software, such as REVEL, suggested that the c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T site mutation was relatively benign, whereas the c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A site mutation had a higher probability of being pathogenic. Further analysis based on family history revealed that the c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T variant is a synonymous mutation located outside the functional domain of the SASH1 gene and distant from the exon boundaries, thus having minimal impact on gene splicing. Moreover, none of the patient's parents or other relatives exhibited phenotypic manifestations, indicating that this site lacks sufficient evidence for being pathogenic. Given the insufficient evidence of pathogenicity for the c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T mutation and the presence of typical clinical manifestations of GL in the patient, combined with the novelty and potentially pathogenic nature of the c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A mutation, which is likely to be inherited in a dominant manner, it is concluded that the c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A mutation carries a higher risk of being transmitted to offspring.\u003c/p\u003e \u003cp\u003eTo date, only 20 cases of GL (male: female\u0026thinsp;=\u0026thinsp;15: 8, age range 2\u0026ndash;40, sporadic: familial\u0026thinsp;=\u0026thinsp;9:13) have been identified to be associated with mutations in the SASH1 gene, with a total of 18 pathogenic mutation sites identified (contains the type of gene mutation: Missense, Frameshift and Duplication) (as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Some research statistics indicate that the SLY domain contains more than 70% of the SASH1 variants related to pigmentary disorders\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. In this study, most SASH1 gene mutation sites are distributed within the SLY domain\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. For instance, the pathogenic mutation site in this patient is located in exon 14 (part of the SLY domain), while non-pathogenic mutations are found in exon 10 (non-functional region); further analysis suggests that mutations leading to functional abnormalities in the SLY domain may be closely linked to the development of GL. Compared to other cases, this case is unique for having dual mutations in the SASH1 gene; one of these new mutations was identified in the family. Non-pathogenic mutations inherited from parents might influence the stability of the SASH1 gene. These mutations could lead to new mutations under genetic, lifestyle, or environmental changes. The age range of patients with GL is quite broad, reaching up to 40 years old without any other systemic damage. The onset of this disease may occur early in life, but systemic lesions often manifest later in adulthood or even later. The specific age at which these changes occur remains uncertain, necessitating lifelong follow-up monitoring.\u003c/p\u003e \u003cp\u003eIn summary, this study identifies for the first time a novel double mutation in the SASH1 gene from a sporadic case of GL using whole exome sequencing technology. Through family investigation, researchers determined the pathogenic mutation (c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A) while excluding the non-pathogenic mutation (c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T). This marks the first report of the novel pathogenic mutation SASH1 (c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A), which may cause both GL and unilateral renal hypoplasia. This discovery not only enriches the human gene mutation database but also provides valuable information for genetic counseling of affected individuals. Currently, there is no specific treatment for GL; thus, early diagnosis, comprehensive health assessments, and early interventions for extracutaneous systemic damage are critical to improving prognosis. It is recommended to establish long-term management and follow-up protocols to control existing symptoms and prevent future health issues.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStatistics on GL cases related to mutations in the SASH1 gene.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAuthor/Years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEthnicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAge at diagnosis (Age at onset)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInheritance(Family member with the same mutation)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVariant type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOther system damage\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eShellman et al\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e.(2015)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSpanish\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e/\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFamilial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1556G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Ser519Asn)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eZhang J et al\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.(2016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eChinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 years(after birth)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1527_1530dupAAGT (p.Leu511Lysfs*21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 years(3 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFamilial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1537A\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ser513Arg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWang Jianbo et al\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.(2016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 years(18 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFamilial(mother)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1519T\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Ser507Ala)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e6\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eZhang Tianjiao et al\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.(2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eChinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 years(3 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1526_1527insAAGT (p.Leu511Lysfs*21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 years(6 months )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1520C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Ser507Phe)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 years(6 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1761C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Ser587Arg)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e9\u0026ndash;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eYuta Araki et al\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.(2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eJapanese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 years(14 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1758C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Iie586Met)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 years(2 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFamilial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1592C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Ser531Yyr)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 years(2 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1574C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Thr525Arg)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 years(8 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1547G\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Ser516IIe)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 years(3 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFamilial(father)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1930C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg644Trp)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u0026ndash;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLi Bo et al\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e.(2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 years(4 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFamilial(father)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.49_54dupCCCGAG (p. P17_E18dup)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDuplication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e17\u0026ndash;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eJae Yeon Kim et al\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.(2023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eKorean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 years(8 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFamilial(father)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1528A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Ser510Cys)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 years(after birth)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1574C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Thr525IIe)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e20\u0026ndash;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eKexin Guo et al\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.(2023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eChinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 years(after birth)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1548T\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Ser516Arg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40 years(after birth)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1811C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Thr604Lys)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThis study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 years(after birth)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSporadic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T(p.Thr343=) and c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A(p.Ser522Arg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eUnilateral renal dysplasia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by Ethics Committee of Affiliated Hospital of Zunyi Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJiang Du Collect clinical data and wrote the papers. Guobiao Liang and Tao Wu Guided the treatment and reviewed manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSHELLMAN Y G, LAMBERT K A, BRAUWEILER A, et al. SASH1 Is Involved in an Autosomal Dominant Lentiginous Phenotype[J]. The Journal of investigative dermatology, 2015, 135(12): 3192-4.\u003c/li\u003e\n\u003cli\u003eSANNA-CHERCHI S, WESTLAND R, GHIGGERI G M, et al. Genetic basis of human congenital anomalies of the kidney and urinary tract[J]. The Journal of clinical investigation, 2018, 128(1): 4-15.\u003c/li\u003e\n\u003cli\u003eBURGESS J T, BOLDERSON E, ADAMS M N, et al. SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer[J]. Scientific reports, 2020, 10(1): 18605.\u003c/li\u003e\n\u003cli\u003eZHANG J, CHENG R, LIANG J, et al. Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination[J]. Clinical genetics, 2016, 90(4): 372-7.\u003c/li\u003e\n\u003cli\u003eWANG J, ZHANG J, LI X, et al. A Novel De novo Mutation of the SASH1 Gene in a Chinese Family with Multiple Lentigines[J]. Acta dermato-venereologica, 2017, 97(4): 530-1.\u003c/li\u003e\n\u003cli\u003eCUI H, GUO S, HE H, et al. SASH1 promotes melanin synthesis and migration via suppression of TGF-\u0026beta;1 secretion in melanocytes resulting in pathologic hyperpigmentation[J]. International journal of biological sciences, 2020, 16(7): 1264-73.\u003c/li\u003e\n\u003cli\u003eVELAYUTHAM R, AHMED A S. LEOPARD syndrome with hypertrophic cardiomyopathy [J]. QJM : monthly journal of the Association of Physicians, 2023, 116(5): 375-6.\u003c/li\u003e\n\u003cli\u003eCHEN Yusha, ZOU Meirong, SONG Deyu, et al. A Case of LEOPAＲD Syndrome Caused by PTPN11 Gene Mutation[J].Chin J Dermatovenereol. 2021, 35(08): 904-7.\u003c/li\u003e\n\u003cli\u003eDIGILIO M C, SARKOZY A, DE ZORZI A, et al. LEOPARD syndrome: clinical diagnosis in the first year of life[J]. American journal of medical genetics Part A, 2006, 140(7): 740-6.\u003c/li\u003e\n\u003cli\u003eZHANG J, LI M, YAO Z. Updated review of genetic reticulate pigmentary disorders[J]. The British journal of dermatology, 2017, 177(4): 945-59.\u003c/li\u003e\n\u003cli\u003eMURTHY A B, PALANIAPPAN V, KARTHIKEYAN K, et al. Dyschromatosis universalis hereditaria[J]. International journal of dermatology, 2023, 62(10): 1218-27.\u003c/li\u003e\n\u003cli\u003eCLEMENTS C M, V\u0026ouml;GELI B, SHELLMAN Y G, et al. Solution NMR backbone assignment of the SASH1 SLy proteins associated disordered region (SPIDER) [J]. Biomolecular NMR assignments, 2023, 17(1): 151-7.\u003c/li\u003e\n\u003cli\u003eGUO K, LIU J W, ZHANG R, et al. Genetic and phenotypic heterogeneity of multiple lentigines and precise diagnosis in four Chinese families with multiple lentigines [J]. Pigment cell \u0026amp; melanoma research, 2023, 36(3-4): 288-98.\u003c/li\u003e\n\u003cli\u003eZHANG Tian-jiao, YANG Xiu-min, WEI Ai-hua. Study on SASH1 genetic mutations in 3 patients of generalized lentiginosis[J]. Journal of Practical Dermatology. 2020, 13(06): 333-6.\u003c/li\u003e\n\u003cli\u003eARAKI Y, OKAMURA K, SAITO T, et al. Five novel mutations in SASH1 contribute to lentiginous phenotypes in Japanese families [J]. Pigment cell \u0026amp; melanoma research, 2021, 34(2): 174-8.\u003c/li\u003e\n\u003cli\u003eLi Bo, Wen Guangdong, Yu Cong, et al. Gene mutation analysis of a family with familial generalized lentiginosis. Chinese Journal of Dermatology [J]. 2022, 55(2): 146-9.\u003c/li\u003e\n\u003cli\u003eKIM J Y, KWON I J, LEE S E. Two novel mutations in SASH1 identified in a familial and a sporadic generalized lentiginosis phenotype in Koreans [J]. Clinical and experimental dermatology, 2023, 48(10): 1171-3.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"SASH1, gene mutation, generalized lentiginosis, unilateral renal dysplasia","lastPublishedDoi":"10.21203/rs.3.rs-4393712/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4393712/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA 19-year-old female patient, diagnosed with generalized lentiginosis and the right renal dysplasia, had all other systems found to be normal. Whole exome sequencing identified double heterozygous missense mutations, c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T and c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A, in the SASH1 gene. Her parents each carry a single-site mutation, c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T, and do not exhibit the similar lentiginous phenotype. According to the literature, both mutation sites are unprecedented, with the c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A variation representing a novel occurrence within this lineage. The primary pathogenic mutation was identified at c.1566C\u0026thinsp;\u0026gt;\u0026thinsp;A, while the evidence for the pathogenicity of c.1029C\u0026thinsp;\u0026gt;\u0026thinsp;T remains insufficient. There are currently no reported cases in the literature where this gene mutation has led to such symptoms. This finding not only contributes to the expansion of the human gene mutation repository but also provides crucial insights for the genetic counseling of the patient and her relatives. During these consultations, it is essential to elucidate the characteristics and implications of these mutations to accurately gauge the patient's risk factors and inform future familial health decisions.\u003c/p\u003e","manuscriptTitle":"A novel double mutation of SASH1 associated with Generalized Lentiginosis and unilateral renal dysplasia: pedigree survey and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-23 18:38:54","doi":"10.21203/rs.3.rs-4393712/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"286a55f2-741d-4d63-9fe1-ac43a7826d54","owner":[],"postedDate":"May 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-19T12:27:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-23 18:38:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4393712","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4393712","identity":"rs-4393712","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}