A Novel NIPBL Variant Causes Cornelia de Lange Syndrome with horseshoe kidney and renal insufficiency: case report and literature review

A Novel NIPBL Variant Causes Cornelia de Lange Syndrome with horseshoe kidney and renal insufficiency: case report 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 Research Article A Novel NIPBL Variant Causes Cornelia de Lange Syndrome with horseshoe kidney and renal insufficiency: case report and literature review Han Yuan, Zhao Fei, Zhu Chunhua This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4283604/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 Background: Renal involvement is rare reported in Cornelia de Lange Syndrome (CdLS). Herein, we present one male boy who is diagnosed as CdLS that have renal involvement with findings related to the novel NIPBL variant. Case presentation:  One male boy was referred to our department because of short stature. He had synophrys with arched and thick eyebrows, long eyelashes, long philtrum. He also had short digits of the thumbs and fifth digits. Renal sonography showed horseshoe kidney. The latest serum creatine was elevated to 64.8umol/L, and eGFR (estimated Glomerular Filtration Rate) was decreased to 76.62 ml/[min·(1.73 m 2 )] (height=136cm). Then whole-exome sequencing showed a de novo frameshift variant of NIPBL gene (NM_133433.4: exon 47，c.8325_8326delAA，p.K2775Nfs*7) in our patient. He was diagnosed as Cornelia de Lange Syndrome. Conclusions: We described a novel frameshift NIPBL variant that causes non-classical CdLS with horseshoe kidney and renal insufficiency. Malformation of the kidney and urinary tract may also have major clinical implications for the diagnosis and genotype–phenotype correlation of NIPBL need further investigation.  Cornelia de Lange syndrome kidney NIPBL Frameshift mutation Introduction Case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Cornelia de Lange syndrome (CdLS) is a rare genetically heterogeneous congenital multisystemic disorder that caused by pathogenic variants of genes encoding the cohesin complex pathway[1]. It was first described by de Lange in 1933. The overall prevalence is estimated to be approximately between 1 in 10,000 and 1 in 30,000 live births[2, 3]. The typical clinical features include short stature, distinctive craniofacial appearance (synophrys, highly arched and/or thick eyebrows，long eyelashes, long philtrum, thin upper lip, depressed nasal bridge and low-set posteriorly rotated ears), hypertrichosis，upper-limb deficiencies and behavioral abnormality [4]. The manifestations of this disorder vary widely and range from relatively mild to severe. Approximately 60%~70% of patients with CdLS have pathogenetic variants in the NIPBL gene (the human Nipped-B liked gene), which plays important roles in cohesion activities and in regulation of other genes [1, 5]. About 5%~10% of cases have disease-causing mutations in SMC1A, SMC3, RAD21, BRD 4 or HDAC8 gene[1, 5]. Genotype–phenotype correlations in individuals with pathogenic gene variants are still unclear. In 2018, a large international group published a first international consensus statement for the diagnosis and management of Cornelia de Lange syndrome[1]. In this statement, renal malformation wasn’t included in the clinical diagnostic criteria. And to date, there are few reports about the renal malformation in patients of CdLS. In this study, we present the additional clinical renal findings of a Chinese male boy with CdLS and reported a novel de novo heterozygous pathogenic variant of the NIPBL gene. Case presentation This male boy is the only child of healthy nonconsanguineous parents with normal heights (father 176cm, mother 158cm) and no known genetic defects or familiar diseases. Both his father and mother have normal birth weight and postnatal growth. He was born at a gestational age of 38 weeks after an uncomplicated delivery. His weight was about 2500 grams, length was not measured at birth. At the age of 8 years old, he was referred to local hospital for treatment of short stature. Then he was treated with growth hormone for more than two years, but there was no effect. At age 12, his height was 129.4cm (-3SD), his body weight was 24.5kg (-2SD) and his occipitofrontal circumference was 52 cm, indicating growth retardation. Then he was referred to our hospital and an extensive medical screening was performed. He had a distinctive craniofacial appearance: synophrys with arched and thick eyebrows, long eyelashes, long philtrum (Figure1). He also had short digits of the thumbs and fifth digits（Figure2）. His cognitions and behaviors were normal. Otorhinolaryngologic and ophthalmologic examinations showed no abnormalities except drooping of his left eyelid（Figure1）. His karyotype was 46, XY. Echocardiography showed a structurally normal heart with normal cardiac function. Renal sonography showed horseshoe kidney（Figure3）. At that time, his serum creatine was normal. But two years later, his serum creatine was elevated to 64.8umol/L, and eGFR (estimated Glomerular Filtration Rate) was decreased to 76.62 ml/[min·(1.73 m 2 )] (height=136cm). According to the criteria proposed in the first international consensus statement of CdLS[1], this patient received a clinical score of 6, indicating molecular testing for CdLS. WES (whole-exome sequencing) in the family trios identified a de novo frameshift variant of NIPBL (NM_133433.4: exon 47，c.8325_8326delAA，p.K2775Nfs*7) in the patient, which was validated by Sanger sequencing (Figure4). To date, this variant has not been cited in gnomAD (https://gnomad.broadinstitute.org/), Clinvar (http://www.ncbi. nlm.nih.gov/clinvar), iJGVD (https://jmorp.megabank.tohoku.ac.jp/ijgvd/), and HGMD (http://www.hgmd.cf.ac.uk/ac/index.php). But this frameshift mutation was predicted to cause the loss of function of NIPBL which can cause CdLS. Thus, rule PVS1 was applied according to the ACMG guidelines. The de novo mutation met rule PS2, as well as rule PM2. Overall, this variant was classified as pathogenic (rules PVS1, PS2 and PM2) according to the American College of Medical Genetics and Genomics criteria [6]. So the patient was diagnosed as Cornelia de Lange Syndrome. Discussion and Conclusion In the present study, we provided two important findings of a male child with CdLS. First, in our study, the child had non-classical and mild clinical features according to the international CdLS consensus [1]，but have additional renal involvement that it isn’t included in the CdLS criteria. Second，We identified a novel heterozygous variant (c.8325_8326delAA) in the NIPBL gene, which was predicted to be pathogenic. This finding expanded the spectrum of pathogenic mutations for CdLS and provided evidence as to whether the diagnosis of CdLS. CdLS is a multisystem malformation syndrome recognized primarily based on the morphological characteristics [7]. The presentation of CdLS can vary widely, from mild to severe and with different degrees of facial and limb involvement. Classic CdLS is easily recognized by experienced pediatricians and clinical geneticists because of a distinctive craniofacial appearance, growth retardation and limb malformations, and classic clinical features may contribute to the prenatal diagnosis [3, 8]. But it may be difficult to diagnosis milder or non-classic phenotypes based on physical features. Considering of the great phenotypic variability of CdLS and the wide heterogeneity in diagnostics, a group of international experts, representing the Scientific Advisory Council of the World Federation of CdLS Support Groups, established an International CdLS Consensus Group to present recommendations for the diagnosis and management of CdLS in 2018 [1]. According to this consensus, our patient received a clinical score of 6, including two cardinal features (synophrys with arched and thick eyebrows, long philtrum) and two suggestive features (postnatal growth retardation, short digits of the thumbs and fifth digits). But our patient had additional features，that are horseshoe kidney and renal insufficiency. Furthermore, trio WES was performed on the boy and his parents to clarify the diagnosis. We identified a novel heterozygous variant (c.8325_8326delAA) in the NIPBL gene. This frameshift mutation was predicted to cause the loss of function of NIPBL. The NIPBL gene consists of 47 exons and is currently considered the cohesin loader, which regulates the loading of the ring of the cohesin complex onto chromatin [9]. Up to 60%~70% of CdLS cases carry heterozygous mutations in NIPBL. Haploinsufficiency caused by loss-of-function variants in the NIPBL gene is thought to be the most common cause of CdLS [10, 11]. And additionally, gene mutations affecting RNA transcription and proteins, such as frameshift mutations, have been found in patients with severe phenotypes of CdLS. It has been known that genotype-phenotype correlation exists on NIPBL. One study of NIPBL mutational analysis in 120 individuals showed that CdLS patients who have no mutation may have a milder phenotypes than patients who have the gene mutation, and patients who have missense mutations have a milder phenotypes than patients who have truncating mutations, which suggests NIPBL as a dosage-sensitive gene [10]. Our patient was diagnosed as CdLS by identifying a novel mutation of NIPBL gene. This frameshift mutation generates a prematurely truncated protein, which could result in NIPBL haploinsufficiency, inducing severe phenotype. But inconsistent with expectation, our patient had non-classical and mild clinical features according to the international CdLS consensus [1]. In addition, our patient had renal malformation and renal insufficiency. These findings suggest that maybe genotype–phenotype correlation of NIPBL in CdLS is still unclear, or maybe renal involvement is one of the severe phenotypes of NIPBL. Interestingly, it had been reported that NIPBL is strongly expressed in fetal and adult kidney, and NIPBL involves the developing kidney in human embryonic tissue sections [12]. But there are only few reports about renal involvement in CdLS patients. Furthermore，renal involvement wasn’t included in the clinical diagnostic criteria of the first international consensus statement for the diagnosis and management of CdLS [6]. In this case, it may result that the clinicians underestimate the value of renal malformation and renal impairment for the diagnosis and management of CdLS patients. In 1982，Wick MR et al first reported an infant have renal malformation with CdLS [13]. But to date, there was only one cross sectional study to evaluate the congenital anomalies of the kidney and urinary tract in CdLS, which was published in 2005 [14]. In that study, Sixty-one Italian patients of CdLS from 61 different families underwent a careful renal and urological evaluation. Twenty-five patients (41%) were diagnosed as structural anomalies of the kidney and urinary tract by ultrasound or voiding cystourethrography, including absent or poor corticomedullary differentiation, pelvic dilation, vesicoureteral reflux, small kidney, isolated renal cyst and renal ectopia. Renal function was reduced in 9 patients with renal tract abnormalities. The anomalies of the kidney and urinary tract and renal functional impairment more frequently occurred in patients with the classic rather than the mild clinical phenotype. These results suggested that anomalies of the kidney and urinary tract are maybe common in CdLS patients. But it is to be regretted that since 2005, only Jaiprakash and his colleague reported a female child of CdLS additionally had multicystic dysplastic kidneys[15]. By investigating 26 Chinese cases of CdLS, no one got the kidney and urinary tract ultrasound[16]. Schrier et al retrospectively reviewed a total of 426 propositi with confirmed clinical diagnoses of CdLS in their database who died in a 41-year period between 1966 and 2007 [17]. They found that renal disease accounted for 1.7% of deaths[17]. According to available literature, our patient had additional clinical manifestations compared with previously described that have not been mentioned in previously reported cases. In the present study, there is no significant family history with respect to renal or renal tract abnormalities and kidney disease. So, it suggested that the horseshoe kidney and renal insufficiency are related to the novel mutation of NIPBL gene, and maybe the pivotal manifestations in the patients of CdLS. Additionally, impaired renal function in this child may indicate that renal disease might progress to end-stage renal disease. Based on these data, clinicians need to pay attention on the analysis of renal involvement in CdLS, then to confirm the value of renal involvement in the diagnosis and management of CdLS. In conclusion, we described a novel NIPBL variant that causes Cornelia de Lange Syndrome with horseshoe kidney and renal insufficiency. The patient harbored a frameshift mutation but had non-classical and mild clinical features. It suggests that anomalies of the kidney and urinary tract may also have major clinical implications for the diagnosis of CdLS and genotype–phenotype correlation of NIPBL need further investigation. Once the clinical diagnosis of CdLS has been confirmed, the patient needs to be evaluated for kidney and urinary tract anomalies by ultrasound that require management or surveillance. And renal function should be monitored in CdLS with structural renal malformations. It needs further studies to confirm whether the renal malformation is one of the cardinal features in CdLS. Abbreviations CdLS Cornelia de Lange Syndrome NIPBL the human Nipped-B liked WES whole-exome sequencing Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. Availability of data and material Not applicable. Competing interests All the authors have read and understood the “Italian Journal of Pediatrics” policy on the declaration of interest and declare that we have no competing interests. Funding This work was supported by the National Key R&D Program of China (No. 2021YFC2702002, 2022YFC2705100), Key R&D Projects of Jiangsu Province (social development, No. BE2021607), and National Clinical Research Center for Child Health and Disorders (No. NCRCCHD-2020-GP-01). Authors' contributions ZCH: ideating and writing the article; HY: writing the article; ZF: ideating and reviewing the article. All authors read and approved the final manuscript. Acknowledgements Thanks to our patient enrolled in the study and their guardians. 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Peng Y, Liang C, Xi H, Yang S, Hu J, Pang J, Liu J, Luo Y, Tang C, Xie W. Wang. Case Report: Novel NIPBL Variants Cause Cornelia de Lange Syndrome in Chinese Patients. Front Genet. 2021;12:699894. https://doi.org/10.3389/fgene.2021.699894 . Boyle MI, Jespersgaard C, Brondum-Nielsen K, Bisgaard AM. Tumer. Cornelia de Lange syndrome. Clin Genet. 2015;88:1–12. https://doi.org/10.1111/cge.12499 . Sarogni P, Pallotta MM, Musio A. Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach. J Med Genet. 2020;57:289–95. https://doi.org/10.1136/jmedgenet-2019-106277 . Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. https://doi.org/10.1038/gim.2015.30 . Parenti I, Kaiser FJ. Cornelia de Lange Syndrome as Paradigm of Chromatinopathies. Front Neurosci. 2021;15:774950. https://doi.org/10.3389/fnins.2021.774950 . Clark DM, Sherer I, Deardorff MA, Byrne JL, Loomes KM, Nowaczyk MJ, Jackson LG, Krantz ID. Identification of a prenatal profile of Cornelia de Lange syndrome (CdLS): a review of 53 CdLS pregnancies. Am J Med Genet A. 2012;158A:1848–56. https://doi.org/10.1002/ajmg.a.35410 . Alonso-Gil D, Losada A. NIPBL and cohesin: new take on a classic tale. Trends Cell Biol. 2023;33:860–71. https://doi.org/10.1016/j.tcb.2023.03.006 . Gillis LA, McCallum J, Kaur M, DeScipio C, Yaeger D, Mariani A, Kline AD, Li HH, Devoto M, Jackson LG, Krantz ID. NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am J Hum Genet. 2004;75:610–23. https://doi.org/10.1086/424698 . Newkirk DA, Chen YY, Chien R, Zeng W, Biesinger J, Flowers E, Kawauchi S, Santos R, Calof AL, Lander AD, Xie X, Yokomori K. The effect of Nipped-B-like (Nipbl) haploinsufficiency on genome-wide cohesin binding and target gene expression: modeling Cornelia de Lange syndrome. Clin Epigenetics. 2017;9. 89.https://doi.org/10.1186/s13148-017-0391-x . Tonkin ET, Wang TJ, Lisgo S, Bamshad MJ, Strachan T. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet. 2004;36:636–41. https://doi.org/10.1038/ng1363 . Wick MR, Simmons PS, Ludwig J, Kleinberg F. Duodenal obstruction, annular pancreas, and horseshoe kidney in an infant with Cornelia de Lange syndrome. Minn Med.1982;65: 539 – 41. Selicorni A, Sforzini C, Milani D, Cagnoli G, Fossali E, Bianchetti MG. Anomalies of the kidney and urinary tract are common in de Lange syndrome. Am J Med Genet A. 2005;132A:395–7. https://doi.org/10.1002/ajmg.a.30445 . Meghwal JN, Arya A, Karnawat BS, Narayan S. Cornelia de Lange syndrome with additional clinical features and multicystic kidney disease. Indian J Pediatr. 2014;81:194–5. .https://doi.org/10.1007/s12098-012-0950-2 . Li S, Miao H, Yang H, Wang L, Gong F, Chen S, Zhu H, Pan H. A report of 2 cases of Cornelia de Lange syndrome (CdLS) and an analysis of clinical and genetic characteristics in a Chinese CdLS cohort. Mol Genet Genomic Med. 2020;8:e1066. .https://doi.org/10.1002/mgg3.1066 . Schrier SA, Sherer I, Deardorff MA, Clark D, Audette L, Gillis L, Kline AD, Ernst L, Loomes K, Krantz ID, Jackson LG. Causes of death and autopsy findings in a large study cohort of individuals with Cornelia de Lange syndrome and review of the literature. Am J Med Genet A. 2011;155A:3007–24. https://doi.org/10.1002/ajmg.a.34329 . 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2","display":"","copyAsset":false,"role":"figure","size":29076,"visible":true,"origin":"","legend":"\u003cp\u003eImages of the hands showing short digits of the thumbs and fifth digits.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4283604/v1/d0fdd15b2aad4c316c7a1930.jpeg"},{"id":66814461,"identity":"1d962964-2d5b-4412-b5c3-d7400b7eb7b7","added_by":"auto","created_at":"2024-10-16 18:01:43","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":13864,"visible":true,"origin":"","legend":"\u003cp\u003eImages of the renal sonography （horseshoe kidney）.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4283604/v1/893812bb06b77484719d3c9d.jpeg"},{"id":66814969,"identity":"d17b7094-dd5c-4197-b8f5-7505b38d5bae","added_by":"auto","created_at":"2024-10-16 18:09:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":25419,"visible":true,"origin":"","legend":"\u003cp\u003eResults of WES show that mutation from affected individuals and wild type from unaffected family members.\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4283604/v1/4ea3109e0abc399ab956bd53.png"},{"id":84279998,"identity":"7489e121-4e44-4154-a5b5-2c728d6254e6","added_by":"auto","created_at":"2025-06-10 06:27:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":665245,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4283604/v1/d174d3f3-90e1-4b03-88b3-2912cf28778c.pdf"},{"id":66814462,"identity":"d6fbb786-9a84-4efc-b968-0b0d3164ff39","added_by":"auto","created_at":"2024-10-16 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typical clinical features include short stature, distinctive craniofacial appearance (synophrys, highly arched and/or thick eyebrows，long eyelashes, long philtrum, thin upper lip, depressed nasal bridge and low-set posteriorly rotated ears), hypertrichosis，upper-limb deficiencies and behavioral abnormality [4]. The manifestations of this disorder vary widely and range from relatively mild to severe. Approximately 60%~70% of patients with CdLS have pathogenetic variants in the NIPBL gene (the human Nipped-B liked gene), which plays important roles in cohesion activities and in regulation of other genes [1, 5]. About 5%~10% of cases have disease-causing mutations in SMC1A, SMC3, RAD21, BRD 4 or HDAC8 gene[1, 5].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGenotype\u0026ndash;phenotype correlations in individuals with pathogenic gene variants are still unclear. In 2018, a large international group published a first international consensus statement for the diagnosis and management of Cornelia de Lange syndrome[1]. In this statement, renal malformation wasn\u0026rsquo;t included in the clinical diagnostic criteria. And to date, there are few reports about the renal malformation in patients of CdLS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this study, we present the additional clinical renal findings of a Chinese male boy with CdLS and reported a novel de novo heterozygous pathogenic variant of the NIPBL gene.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThis male boy is the only child of healthy nonconsanguineous parents with normal heights (father 176cm, mother 158cm) and no known genetic defects or familiar diseases. Both his father and mother have normal birth weight and postnatal growth. He was born at a gestational age of 38 weeks after an uncomplicated delivery. His weight was about 2500 grams, length was not measured at birth. At the age of 8 years old, he was referred to local hospital for treatment of short stature. Then he was treated with growth hormone for more than two years, but there was no effect. At age 12, his height was 129.4cm (-3SD), his body weight was 24.5kg (-2SD) and his\u0026nbsp;occipitofrontal circumference was 52 cm, indicating growth retardation. Then he was referred to our hospital and an extensive medical screening was performed. He had a distinctive craniofacial appearance: synophrys with arched and thick eyebrows, long eyelashes, long philtrum (Figure1). He also had short digits of the thumbs and fifth digits（Figure2）. His cognitions and behaviors were normal. Otorhinolaryngologic and ophthalmologic examinations showed no abnormalities except drooping of his left eyelid（Figure1）. His karyotype was 46, XY. Echocardiography showed a structurally normal heart with normal cardiac function.\u0026nbsp;Renal sonography showed\u0026nbsp;horseshoe kidney（Figure3）. At that time, his serum creatine was normal. But two years later, his serum creatine was elevated to 64.8umol/L, and eGFR (estimated Glomerular Filtration Rate) was decreased to 76.62 ml/[min\u0026middot;(1.73 m\u003csup\u003e2\u003c/sup\u003e)] \u0026nbsp;(height=136cm).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAccording to the criteria proposed in the first international consensus statement of CdLS[1], this patient received a clinical score of 6, indicating molecular testing for CdLS. \u0026nbsp;WES (whole-exome sequencing) in the family trios identified a de novo frameshift variant of NIPBL (NM_133433.4: exon 47，c.8325_8326delAA，p.K2775Nfs*7) in the patient, which was validated by Sanger sequencing (Figure4). To date, this variant has not been cited in gnomAD (https://gnomad.broadinstitute.org/), Clinvar (http://www.ncbi. nlm.nih.gov/clinvar), iJGVD (https://jmorp.megabank.tohoku.ac.jp/ijgvd/), and HGMD (http://www.hgmd.cf.ac.uk/ac/index.php). But this frameshift mutation was predicted to cause the loss of function of NIPBL which can cause CdLS. Thus, rule PVS1 was applied according to the ACMG guidelines. The de novo mutation met rule PS2, as well as rule PM2. Overall, this variant was classified as pathogenic (rules PVS1, PS2 and PM2) according to the American College of Medical Genetics and Genomics criteria [6]. So the patient was diagnosed as Cornelia de Lange Syndrome.\u003c/p\u003e"},{"header":"Discussion and Conclusion","content":"\u003cp\u003eIn the present study, we provided two important findings of a male child with CdLS. First, in our study, the child had non-classical and mild clinical features according to the international CdLS consensus [1]，but have additional renal involvement that it isn\u0026rsquo;t included in the CdLS criteria. Second，We identified a novel heterozygous variant (c.8325_8326delAA) in the NIPBL gene, which was predicted to be pathogenic. This finding expanded the spectrum of pathogenic mutations for CdLS and provided evidence as to whether the diagnosis of CdLS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCdLS is a multisystem malformation syndrome recognized primarily based on the morphological characteristics [7]. The presentation of CdLS can vary widely, from mild to severe and with different degrees of facial and limb involvement. Classic CdLS is easily recognized by experienced pediatricians and clinical geneticists because of a distinctive craniofacial appearance, growth retardation and limb malformations, and classic clinical features may contribute to the prenatal diagnosis [3, 8]. But it may be difficult to diagnosis milder or non-classic phenotypes based on physical features. Considering of the great phenotypic variability of CdLS and the wide heterogeneity in diagnostics, a group of international experts, representing the Scientific Advisory Council of the World Federation of CdLS Support Groups, established an International CdLS Consensus Group to present recommendations for the diagnosis and management of CdLS in 2018 [1]. According to this consensus, our patient received a clinical score of 6, including two cardinal features (synophrys with arched and thick eyebrows, long philtrum) and two suggestive features (postnatal growth retardation, short digits of the thumbs and fifth digits). But our patient had additional features，that are horseshoe kidney and renal insufficiency.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, trio WES was performed on the boy and his parents to clarify the diagnosis. We identified a novel heterozygous variant (c.8325_8326delAA) in the NIPBL gene. This frameshift mutation was predicted to cause the loss of function of NIPBL. The NIPBL gene consists of 47 exons and is currently considered the cohesin loader, which regulates the loading of the ring of the cohesin complex onto chromatin [9]. Up to 60%~70% of CdLS cases carry heterozygous mutations in NIPBL. Haploinsufficiency caused by loss-of-function variants in the NIPBL gene is thought to be the most common cause of CdLS [10, 11]. And additionally, gene mutations affecting RNA transcription and proteins, such as frameshift mutations, have been found in patients with severe phenotypes of CdLS. It has been known that genotype-phenotype correlation exists on NIPBL. One study of NIPBL mutational analysis in 120 individuals showed that CdLS patients who have no mutation may have a milder phenotypes than patients who have the gene mutation, and patients who have missense mutations have a milder phenotypes than patients who have truncating mutations, which suggests NIPBL as a dosage-sensitive gene [10]. Our patient was diagnosed as CdLS by identifying a novel mutation of NIPBL gene. This frameshift mutation generates a prematurely truncated protein, which could result in NIPBL haploinsufficiency, inducing severe phenotype. But inconsistent with expectation, our patient had non-classical and mild clinical features according to the international CdLS consensus [1]. In addition, our patient had renal malformation and renal insufficiency. These findings suggest that maybe genotype\u0026ndash;phenotype correlation of NIPBL in CdLS is still unclear, or maybe renal involvement is one of the severe phenotypes of NIPBL.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInterestingly, it had been reported that NIPBL is strongly expressed in fetal and adult kidney, and NIPBL involves the developing kidney in human embryonic tissue sections [12]. But there are only few reports about renal involvement in CdLS patients. Furthermore，renal involvement wasn\u0026rsquo;t included in the clinical diagnostic criteria of the first international consensus statement for the diagnosis and management of CdLS [6]. In this case, it may result that the clinicians underestimate the value of renal malformation and renal impairment for the diagnosis and management of CdLS patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn 1982，Wick MR et al first reported an infant have renal malformation with CdLS [13]. But to date, there was only one cross sectional study to evaluate the congenital anomalies of the kidney and urinary tract in CdLS, which was published in 2005 [14]. In that study, Sixty-one Italian patients of CdLS from 61 different families underwent a careful renal and urological evaluation. Twenty-five patients (41%) were diagnosed as structural anomalies of the kidney and urinary tract by ultrasound or voiding cystourethrography, including absent or poor corticomedullary differentiation, pelvic dilation, vesicoureteral reflux, small kidney, isolated renal cyst and renal ectopia. Renal function was reduced in 9 patients with renal tract abnormalities. The anomalies of the kidney and urinary tract and renal functional impairment more frequently occurred in patients with the classic rather than the mild clinical phenotype. These results suggested that anomalies of the kidney and urinary tract are maybe common in CdLS patients. But it is to be regretted that since 2005, only Jaiprakash and his colleague reported a female child of CdLS additionally had multicystic dysplastic kidneys[15]. By investigating 26 Chinese cases of CdLS, no one got the kidney and urinary tract ultrasound[16]. Schrier et al retrospectively reviewed a total of 426 propositi with confirmed clinical diagnoses of CdLS in their database who died in a 41-year period between 1966 and 2007 [17]. They found that renal disease accounted for 1.7% of deaths[17]. According to available literature, our patient had additional clinical manifestations compared with previously described that have not been mentioned in previously reported cases. In the present study, there is no significant family history with respect to renal or renal tract abnormalities and kidney disease. So, it suggested that the horseshoe kidney and renal insufficiency are related to the novel mutation of NIPBL gene, and maybe the pivotal manifestations in the patients of CdLS. Additionally, impaired renal function in this child may indicate that renal disease might progress to end-stage renal disease. Based on these data, clinicians need to pay attention on the analysis of renal involvement in CdLS, then to confirm the value of renal involvement in the diagnosis and management of CdLS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, we described a novel NIPBL variant that causes Cornelia de Lange Syndrome with horseshoe kidney and renal insufficiency. The patient harbored a frameshift mutation but had non-classical and mild clinical features.\u003c/p\u003e\n\u003cp\u003eIt suggests that anomalies of the kidney and urinary tract may also have major clinical implications for the diagnosis of CdLS and genotype\u0026ndash;phenotype correlation of NIPBL need further investigation. Once the clinical diagnosis of CdLS has been confirmed, the patient needs to be evaluated for kidney and urinary tract anomalies by ultrasound that require management or surveillance. And renal function should be monitored in CdLS with structural renal malformations. It needs further studies to confirm whether the renal malformation is one of the cardinal features in CdLS.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.1007371007371%\" valign=\"top\"\u003e\n \u003cp\u003eCdLS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"62.8992628992629%\" valign=\"top\"\u003e\n \u003cp\u003eCornelia de Lange Syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.1007371007371%\" valign=\"top\"\u003e\n \u003cp\u003eNIPBL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"62.8992628992629%\" valign=\"top\"\u003e\n \u003cp\u003ethe human Nipped-B liked\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.1007371007371%\" valign=\"top\"\u003e\n \u003cp\u003eWES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"62.8992628992629%\" valign=\"top\"\u003e\n \u003cp\u003ewhole-exome sequencing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\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 parents of the patient for publication of this case report and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors have read and understood the \u0026ldquo;Italian Journal of Pediatrics\u0026rdquo; policy on the declaration of interest and declare that we have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Key R\u0026amp;D Program of China (No. 2021YFC2702002, 2022YFC2705100), Key R\u0026amp;D Projects of Jiangsu Province (social development, No. BE2021607), and National Clinical Research Center for Child Health and Disorders (No. NCRCCHD-2020-GP-01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZCH: ideating and writing the article;\u0026nbsp;HY: writing the article;\u0026nbsp;ZF: ideating and reviewing the article. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThanks to our patient enrolled in the study and their guardians.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gillett PM, Ishman SL, Kerr LM, Levin AV, Mulder PA, Ramos FJ, Wierzba J, Ajmone PF, Axtell D, Blagowidow N, Cereda A, Costantino A, Cormier-Daire V, FitzPatrick D, Grados M, Groves L, Guthrie W, Huisman S, Kaiser FJ, Koekkoek G, Levis M, Mariani M, McCleery JP, Menke LA, Metrena A, O'Connor J, Oliver C, Pie J, Piening S, Potter CJ, Quaglio AL, Redeker E, Richman D, Rigamonti C, Shi A, Tumer Z, Van Balkom IDC, Hennekam RC. Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement. 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Indian J Pediatr. 2014;81:194\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e.https://doi.org/10.1007/s12098-012-0950-2\u003c/span\u003e\u003cspan address=\".10.1007/s12098-012-0950-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi S, Miao H, Yang H, Wang L, Gong F, Chen S, Zhu H, Pan H. A report of 2 cases of Cornelia de Lange syndrome (CdLS) and an analysis of clinical and genetic characteristics in a Chinese CdLS cohort. Mol Genet Genomic Med. 2020;8:e1066. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e.https://doi.org/10.1002/mgg3.1066\u003c/span\u003e\u003cspan address=\".10.1002/mgg3.1066\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchrier SA, Sherer I, Deardorff MA, Clark D, Audette L, Gillis L, Kline AD, Ernst L, Loomes K, Krantz ID, Jackson LG. Causes of death and autopsy findings in a large study cohort of individuals with Cornelia de Lange syndrome and review of the literature. Am J Med Genet A. 2011;155A:3007\u0026ndash;24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ajmg.a.34329\u003c/span\u003e\u003cspan address=\"10.1002/ajmg.a.34329\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\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":"Cornelia de Lange syndrome, kidney, NIPBL, Frameshift mutation Introduction, Case report","lastPublishedDoi":"10.21203/rs.3.rs-4283604/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4283604/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eRenal involvement is rare reported in Cornelia de Lange Syndrome (CdLS). Herein, we present one male boy who is diagnosed as CdLS that have renal involvement with findings related to the novel NIPBL variant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eOne male boy was referred to our department because of short stature. He had synophrys with arched and thick eyebrows, long eyelashes, long philtrum. He also had short digits of the thumbs and fifth digits. Renal sonography showed horseshoe kidney. The latest serum creatine was elevated to 64.8umol/L, and eGFR (estimated Glomerular Filtration Rate) was decreased to 76.62 ml/[min·(1.73 m\u003csup\u003e2\u003c/sup\u003e)]\u0026nbsp; (height=136cm). Then whole-exome sequencing showed a de novo frameshift variant of NIPBL gene (NM_133433.4: exon 47，c.8325_8326delAA，p.K2775Nfs*7) in our patient. He was diagnosed as Cornelia de Lange Syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eWe described a novel frameshift NIPBL variant that causes non-classical CdLS with horseshoe kidney and renal insufficiency. Malformation of the kidney and urinary tract may also have major clinical implications for the diagnosis and genotype–phenotype correlation of NIPBL need further investigation. \u003c/p\u003e","manuscriptTitle":"A Novel NIPBL Variant Causes Cornelia de Lange Syndrome with horseshoe kidney and renal insufficiency: case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-16 17:53:39","doi":"10.21203/rs.3.rs-4283604/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":"940be64e-25e7-4af5-a721-8bbbc885beb2","owner":[],"postedDate":"October 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-10T06:19:34+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-16 17:53:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4283604","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4283604","identity":"rs-4283604","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}