Adult Diagnosis of ATN1-Related Neurodevelopmental Disorder: A Case Report of a Mild Phenotype with In-Frame Tandem Duplication in the HX Motif

Adult Diagnosis of ATN1-Related Neurodevelopmental Disorder: A Case Report of a Mild Phenotype with In-Frame Tandem Duplication in the HX Motif | 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 Adult Diagnosis of ATN1-Related Neurodevelopmental Disorder: A Case Report of a Mild Phenotype with In-Frame Tandem Duplication in the HX Motif William McGonigle, Sneha Kapil, Dayna Morel Swols, Deborah Barbouth This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7274724/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Apr, 2026 Read the published version in Current Genetic Medicine Reports → Version 1 posted You are reading this latest preprint version Abstract ATN1-related neurodevelopmental disorder (ATN1-NDD) is a rare genetic condition typically diagnosed in infancy, characterized by profound developmental delay and hypotonia due to heterozygous pathogenic variants in the highly conserved HX motif of the ATN1 gene. We present a unique case of a 29-year-old male with mild intellectual disability, autism spectrum disorder, and microcephaly, diagnosed in adulthood through reclassification of a heterozygous in-frame tandem duplication variant (c.3188_3193dupTGCACC) within the HX motif. This case represents one of the mildest and latest reported presentations of ATN1-NDD, expanding the known phenotypic spectrum. Notably, the patient’s genotype parallels the only other known mild case, suggesting a possible genotype-phenotype correlation distinct from the severe phenotypes typically observed. This report underscores the importance of genetic re-evaluation in adults with unexplained neurodevelopmental disorders and contributes valuable insight into the variability and natural history of ATN1-NDD. CHEDDA ATN-1 intellectual disability autism HX motif neurodevelopmental disorder Introduction ATN1-related neurodevelopmental disorder (ATN1-NDD) is a broad group of rare diseases defined by any neurodevelopmental disorder caused by pathogenic variants within ATN1 , a gene which encodes atrophin-1, a protein involved in transcriptional regulation and brain development [ 1 ]. When the genotypic findings specifically refer to variants in a highly conserved 16-amino-acid segment of exon 7 of ATN1 characterized by a repeating histidine motif (HX motif), the disease has become referred to as CHEDDA syndrome, based on typically seen symptoms of Congenital Hypotonia, Epilepsy, Developmental Delay, and digit Anomalies. The disruption of this motif leads to a recognizable but variable, rare, autosomal dominant neurodevelopmental phenotype, only formally recognized in 2019 [ 2 ]. Within this gene, there exists a different distinct syndrome, dentatorubral-pallidoluysian atrophy (DRPLA), caused by CAG repeats in exon 5 of ATN1 , characterized by movement disorders, cognitive decline, and psychiatric symptoms, with symptoms presenting no earlier than late adulthood [ 3 ]. As of this writing, only 18 individuals have been reported in the literature with genetically confirmed ATN1-NDD specific to the HX motif region [ 1 , 2 , 4 – 7 ]. Most cases present with severe symptoms from birth, including profound developmental and/or intellectual disability, hypotonia, respiratory difficulties, and feeding challenges such as gastroesophageal reflux disease (GERD) and dysphagia, often requiring gastrostomy tube placement [ 4 ]. Additional features observed in approximately half of reported cases include epilepsy, cortical visual impairment, hearing loss, cardiac malformations, and other ophthalmologic anomalies. Genitourinary abnormalities have also been described, though less commonly [ 4 ]. Among the 18 reported cases, all but one exhibited hypotonia and significant gross motor delays, with most patients being nonverbal and demonstrating limited fine motor development [ 1 ]. Notably, one individual was reported to have only mild developmental delay, with no hypotonia, higher levels of fine motor functioning, and the ability to speak in short sentences by 26 months of age [ 4 ]. Here, we present the case of a 29-year-old with lifelong mild intellectual disability, who was diagnosed in adulthood with an ATN1 mutation. To our knowledge, this is among the mildest and latest presentations reported to date [ 1 ]. Through this case, we aim to expand the clinical understanding of ATN1-NDD and highlight the importance of considering this diagnosis even in adults with subtle phenotypes. Case Presentation A 29-year-old male of Cuban and Spanish ancestry presented to the medical genetics clinic for evaluation of autism, microcephaly, and intellectual disability (IQ: 52). Developmentally, he was noted to have intrauterine growth restriction at 6–7 months gestation and was delivered via cesarean section at 42 weeks due to lack of labor progression. The patient had no family history of any developmental disorders. From birth, he experienced significant feeding difficulties and required a gastrostomy tube until 4.5 years of age. Microcephaly was noted early, and at 18 months, a neurologist raised concern for pervasive developmental disorder. At age 5, he was formally diagnosed with autism spectrum disorder and was placed in a specialized educational setting in his school with extra attention. Despite these extra needs, he was reported to progress well academically meeting age-appropriate expectations in this classroom setting. He was considered to have high-functioning autism and is variably verbal, speaking in short sentences to full conversations depending on the topic. Throughout childhood, he exhibited a range of behavioral and psychiatric symptoms, including obsessive-compulsive behaviors, attention-deficit hyperactivity disorder (ADHD), anxiety, aggression, social inappropriateness, and depression. In the year prior to his most recent genetics visit, he was diagnosed with bipolar disorder and began treatment with mood-stabilizing medications, which have improved his affective symptoms. His parents have noted a progressive decline in his ability to retain newly learned information, such as counting money and performing basic multiplication, despite previously being able to learn new skills and at one point was holding a supported employment position in a retail setting. Patient has one sister who has not had any symptoms with which the proband presented. On examination the patient was found to have microcephaly, retrognathia, small ears, and a short philtrum. He was noted to have small hands and feet and syndactyly of toes 1–2 and 2–3. He also had increased deep tendon reflexes and muscle stiffness throughout. The patient has undergone extensive prior evaluations including normal karyotype, fragile X testing, brain MRI, sinus MRI, EEG, metabolic screening (amino acids, organic acids, mucopolysaccharides), and chromosomal microarray prior to presenting at our clinic. At age 20, research-based whole exome sequencing (WES) identified three variants of uncertain significance (VUS), including one in the ATN1 gene. Repeat WES at age 26 reclassified the ATN1 variant as pathogenic: c.3188_3193dupTGCACC (p.L1063_H1064dup), a heterozygous in-frame duplication within the gene’s highly conserved HX motif region. While it is assumed that the patient had a de novo mutation here, no parental tests were done to determine definitively the nature of this variant. Discussion Patients with described CHEDDA syndrome have variants within the region of the C-terminal part of ATN1 (residues 1049–1065) consisting of 8 HX repeats [ 4 ]. This patient’s mutation represents an in-frame duplication of six nucleotides resulting in the insertion of an additional leucine-histidine dipeptide between residues 1063 and 1064. Although the protein remains full-length and the reading frame is preserved, any disruption of the periodic HX motif is believed to underlie the pathogenesis of most cases of ATN1-related neurodevelopmental disorder (ATN1-NDD) localized to this 16-residue segment, as seen in previously reported cases [ 1 , 2 ]. The diagnosis of this patient with ATN1-NDD is distinct for several reasons. As a relatively recently described rare disease, the diagnosis and reporting of new patients has largely been confined to pediatric patients with profound developmental/intellectual delays and symptoms typical of the CHEDDA diagnostic term [ 2 ]. Comparatively, while the patient did present with oral intolerance, microcephaly, and intellectual and developmental delays, the patient is notable for having only mild intellectual disability where he was able to work in a retail store and attend school in a supported capacity. Only one other patient reported was determined to have a mild delay, with all other patients being found to have profound delays [ 1 ]. In addition, he lacked the reported hypotonia and more severe digit abnormalities specific to the CHEDDA designation as well as other commonly seen symptoms including congenital malformations, hearing loss, or respiratory symptoms [ 4 ]. Most significantly, he is the oldest reported patient receiving this diagnosis [ 2 ]. There is little information about the life span of patients with this disease as it was first reported in 2019 and most of the patients now recently diagnosed have been pediatric patients [ 2 ]. This patient who recently turned 30 and presented in relatively good physical health does provide a potential clue into life expectancies of individuals with this disease. However, the generalization of this case to other patients with CHEDDA is limited by the fact that this patient has had a milder disease course since birth. In addition, reports of worsening memory retention in our patient may indicate eventual disease progression and warrants further follow-up and evaluation to better understand the long-term clinical course of CHEDDA. Most mutations have been determined to be de novo mutations in this highly conserved region, consistent with broader findings in adult-onset mendelian disease cohorts where de novo mutations account for over 60% of autosomal dominant diagnoses [ 2 , 8 ]. Interestingly, the only other patient who was noted to have only mild developmental delay regarding both fine and gross motor skills and no hypotonia was found to also have a duplication of the amino acids: histidine and leucine in the HX motif rather than the more typically seen type of mutation of indels or single-nucleotide variants. This genotype is similar to our patient described where instead of an insertion or deletion of random sequences, there is a tandem duplication of the motif with a preserved reading frame [ 2 ]. This case represents only the second reported patient with this unique genotype and a similarly mild presentation. These genotypes may help explain why some individuals with this disease present with milder symptoms, potentially representing a larger population that remains undiagnosed [ 4 ]. While our patient is the first adult patient to be recognized with this rare disease, it has been thought that there are likely more patients with more mild developmental disease similar to our patient who have lived into adulthood [ 1 ]. As we were able to diagnose our patient with this disease through new updates in exome sequencing and variant identification, this gives further support to the importance of variant reclassification and patient follow up through time to determine if any new findings have been reported which could explain their symptoms. In a recent study using genome sequencing after a negative diagnostic evaluation, over half of patients (53.4%) who received a molecular diagnosis could have received the same diagnosis through re-analysis of prior exome-sequencing [ 8 ]. This re-analysis utilizes advances and discoveries in gene-disease relationships further supporting ongoing follow-up of patients with symptoms of unidentified etiologies. Conclusion This case highlights a uniquely mild and adult presentation of ATN1-related neurodevelopmental disorder, a rare condition typically recognized in pediatric patients with profound developmental delays and hypotonia. The patient’s genotype—an in-frame tandem duplication within the HX motif—mirrors the only previously reported individual with a similarly mild phenotype, suggesting a possible genotype-phenotype correlation and wider phenotypic variability within CHEDDA, which is more commonly associated with more severe indels and single-nucleotide variants. This case expands the known clinical spectrum of ATN1-NDD and underscores the importance of reclassifying genetic variants over time. It also supports the consideration of ATN1 testing and genetic re-evaluation in adults with unexplained mild intellectual disability and other syndromic findings. Declarations Funding: The authors did not receive support from any organization for the submitted work. Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article. Consent to Publish: Verbal informed consent was obtained from the patient’s father after detailed explanation of the case report and its intended publication. Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by William McGonigle, Sneha Kapil, Dayna Morel, and Deborah Barbouth. The first draft of the manuscript was written by William McGonigle and Sneha Kapil and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Whitton C, Palmer E, Alkuraya F. ATN1-Related Neurodevelopmental Disorder. In: GeneReviews® [Internet]. National Library of Medicine. 2022. https://www.ncbi.nlm.nih.gov/books/NBK583218/. Accessed 24 July 2025. Palmer EE, Hong S, Al Zahrani F, Hashem MO, Aleisa FA, Ahmed HMJ, Kandula T, Macintosh R, Minoche AE, Puttick C, Gayevskiy V, Drew AP, Cowley MJ, Dinger M, Rosenfeld JA, Xiao R, Cho MT, Yakubu SF, Henderson LB, Guillen Sacoto MJ, Begtrup A, Hamad M, Shinawi M, Andrews MV, Jones MC, Lindstrom K, Bristol RE, Kayani S, Snyder M, Villanueva MM, Schteinschnaider A, Faivre L, Thauvin C, Vitobello A, Roscioli T, Kirk EP, Bye A, Merzaban J, Jaremko Ł, Jaremko M, Sachdev RK, Alkuraya FS, Arold ST. De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome. Am J Hum Genet. 2019; https://doi.org/10.1016/j.ajhg.2019.01.013. Erratum in: Am J Hum Genet. 2019; https://doi.org/10.1016/j.ajhg.2019.03.016. Prades S, Melo de Gusmao C, Grimaldi S, Shiloh-Malawasky Y, Felton T, Houlden H. DRPLA. In: GeneReviews® [Internet]. National Library of Medicine.1999 [Updated 2023]; https://www.ncbi.nlm.nih.gov/books/NBK1491/. Accessed 24 July 2025. Palmer EE, Whitton C, Hashem MO, Clark RD, Ramanathan S, Starr LJ, Velasco D, De Dios JK, Singh E, Cormier-Daire V, Chopra M, Rodan LH, Nellaker C, Lakhani S, Mallack EJ, Panzer K, Sidhu A, Wentzensen IM, Lacombe D, Michaud V, Alkuraya FS. CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum. Clin Genet . 2021; https://doi.org/10.1111/cge.14022 Hui, Jessica, Sedat Giray Kandemirli, and Takashi Shawn Sato. CHEDDA syndrome: A case report and review of the literature for this newly described entity. Radiology Case Reports. 2020; https://doi.org/10.1016/j.radcr.2020.05.079 Luo S, Hu Y, Xiong P, Tan L, Zhao P, Huang Y, Xiao C, Zhu H, He X. A novel variant in the HX repeat motif of ATN1 in a Chinese patient with CHEDDA syndrome and literature review. Molecular Genetics & Genomic Medicine 2022; https://doi.org/10.1002/mgg3.2068. Makarova, E., Legro, N., & Aliu, E. eP185: A novel, milder case of CHEDDA syndrome caused by a de novo variant outside of the canonical HX-motif of ATN1. Genetics in Medicine. 2022; https://doi.org/10.1016/j.gim.2022.01.221. Wojcik MH, Lemire G, Berger E, et al. Genome Sequencing for Diagnosing Rare Diseases. N Engl J Med . 2024; https://doi.org/10.1056/NEJMoa2314761 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 27 Apr, 2026 Read the published version in Current Genetic Medicine Reports → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-7274724","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":499065737,"identity":"01911bb6-a34b-42c1-8326-2119c766f605","order_by":0,"name":"William McGonigle","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYHAC9g8SFUDqABhJAFkJBLWwMVicIVlLZRtECxQQ0GJw/HTag5vztsnxHeBOPPAzx4KBnz3HAL+WM7nbDWduu20seYB3w8HebRIMkj1v8Gsxu8G7QVpy2+3EDUAtB3iBWgxuELAFrOXvnNv1IC0H/wK12BOhZZuEZMPtBAOglsNgWyQIaLE/k7vZQOLYbcOZh4FaZLdJ8EiceVaAV4tk+9mNDyRqbsvzHe/d/PHttjo5/vbkDXi1IAAzhOIhUvkoGAWjYBSMAnwAABAwTs11zU9EAAAAAElFTkSuQmCC","orcid":"","institution":"University of Miami Miller School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"William","middleName":"","lastName":"McGonigle","suffix":""},{"id":499065740,"identity":"725f712b-2148-4d93-8341-e05cb82db13d","order_by":1,"name":"Sneha Kapil","email":"","orcid":"","institution":"University of Miami Miller School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sneha","middleName":"","lastName":"Kapil","suffix":""},{"id":499065741,"identity":"9cfc8503-85d9-4337-a0ec-e6b80a8ec767","order_by":2,"name":"Dayna Morel Swols","email":"","orcid":"","institution":"University of Miami, Jackson Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dayna","middleName":"Morel","lastName":"Swols","suffix":""},{"id":499065742,"identity":"b0001b35-4c26-4cd4-8b49-2252a376c19b","order_by":3,"name":"Deborah Barbouth","email":"","orcid":"","institution":"University of Miami, Jackson Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Deborah","middleName":"","lastName":"Barbouth","suffix":""}],"badges":[],"createdAt":"2025-08-02 00:38:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7274724/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7274724/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s40142-026-00245-6","type":"published","date":"2026-04-27T15:58:08+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":108437795,"identity":"d26b7f3d-c2c7-4995-931a-19a088f4d28a","added_by":"auto","created_at":"2026-05-04 16:03:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":132552,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7274724/v1/f5317d63-a79b-41d2-900f-2a0b8eb9fb43.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adult Diagnosis of ATN1-Related Neurodevelopmental Disorder: A Case Report of a Mild Phenotype with In-Frame Tandem Duplication in the HX Motif","fulltext":[{"header":"Introduction","content":"\u003cp\u003eATN1-related neurodevelopmental disorder (ATN1-NDD) is a broad group of rare diseases defined by any neurodevelopmental disorder caused by pathogenic variants within \u003cem\u003eATN1\u003c/em\u003e, a gene which encodes atrophin-1, a protein involved in transcriptional regulation and brain development [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. When the genotypic findings specifically refer to variants in a highly conserved 16-amino-acid segment of exon 7 of \u003cem\u003eATN1\u003c/em\u003e characterized by a repeating histidine motif (HX motif), the disease has become referred to as CHEDDA syndrome, based on typically seen symptoms of Congenital Hypotonia, Epilepsy, Developmental Delay, and digit Anomalies. The disruption of this motif leads to a recognizable but variable, rare, autosomal dominant neurodevelopmental phenotype, only formally recognized in 2019 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Within this gene, there exists a different distinct syndrome, dentatorubral-pallidoluysian atrophy (DRPLA), caused by CAG repeats in exon 5 of \u003cem\u003eATN1\u003c/em\u003e, characterized by movement disorders, cognitive decline, and psychiatric symptoms, with symptoms presenting no earlier than late adulthood [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAs of this writing, only 18 individuals have been reported in the literature with genetically confirmed ATN1-NDD specific to the HX motif region [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Most cases present with severe symptoms from birth, including profound developmental and/or intellectual disability, hypotonia, respiratory difficulties, and feeding challenges such as gastroesophageal reflux disease (GERD) and dysphagia, often requiring gastrostomy tube placement [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additional features observed in approximately half of reported cases include epilepsy, cortical visual impairment, hearing loss, cardiac malformations, and other ophthalmologic anomalies. Genitourinary abnormalities have also been described, though less commonly [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong the 18 reported cases, all but one exhibited hypotonia and significant gross motor delays, with most patients being nonverbal and demonstrating limited fine motor development [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Notably, one individual was reported to have only mild developmental delay, with no hypotonia, higher levels of fine motor functioning, and the ability to speak in short sentences by 26 months of age [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHere, we present the case of a 29-year-old with lifelong mild intellectual disability, who was diagnosed in adulthood with an \u003cem\u003eATN1\u003c/em\u003e mutation. To our knowledge, this is among the mildest and latest presentations reported to date [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Through this case, we aim to expand the clinical understanding of ATN1-NDD and highlight the importance of considering this diagnosis even in adults with subtle phenotypes.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 29-year-old male of Cuban and Spanish ancestry presented to the medical genetics clinic for evaluation of autism, microcephaly, and intellectual disability (IQ: 52). Developmentally, he was noted to have intrauterine growth restriction at 6–7 months gestation and was delivered via cesarean section at 42 weeks due to lack of labor progression. The patient had no family history of any developmental disorders. From birth, he experienced significant feeding difficulties and required a gastrostomy tube until 4.5 years of age. Microcephaly was noted early, and at 18 months, a neurologist raised concern for pervasive developmental disorder. At age 5, he was formally diagnosed with autism spectrum disorder and was placed in a specialized educational setting in his school with extra attention. Despite these extra needs, he was reported to progress well academically meeting age-appropriate expectations in this classroom setting. He was considered to have high-functioning autism and is variably verbal, speaking in short sentences to full conversations depending on the topic.\u003c/p\u003e\u003cp\u003eThroughout childhood, he exhibited a range of behavioral and psychiatric symptoms, including obsessive-compulsive behaviors, attention-deficit hyperactivity disorder (ADHD), anxiety, aggression, social inappropriateness, and depression. In the year prior to his most recent genetics visit, he was diagnosed with bipolar disorder and began treatment with mood-stabilizing medications, which have improved his affective symptoms. His parents have noted a progressive decline in his ability to retain newly learned information, such as counting money and performing basic multiplication, despite previously being able to learn new skills and at one point was holding a supported employment position in a retail setting. Patient has one sister who has not had any symptoms with which the proband presented.\u003c/p\u003e\u003cp\u003eOn examination the patient was found to have microcephaly, retrognathia, small ears, and a short philtrum. He was noted to have small hands and feet and syndactyly of toes 1–2 and 2–3. He also had increased deep tendon reflexes and muscle stiffness throughout. The patient has undergone extensive prior evaluations including normal karyotype, fragile X testing, brain MRI, sinus MRI, EEG, metabolic screening (amino acids, organic acids, mucopolysaccharides), and chromosomal microarray prior to presenting at our clinic. At age 20, research-based whole exome sequencing (WES) identified three variants of uncertain significance (VUS), including one in the \u003cem\u003eATN1\u003c/em\u003e gene. Repeat WES at age 26 reclassified the \u003cem\u003eATN1\u003c/em\u003e variant as pathogenic: c.3188_3193dupTGCACC (p.L1063_H1064dup), a heterozygous in-frame duplication within the gene’s highly conserved HX motif region. While it is assumed that the patient had a de novo mutation here, no parental tests were done to determine definitively the nature of this variant.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with described CHEDDA syndrome have variants within the region of the C-terminal part of ATN1 (residues 1049\u0026ndash;1065) consisting of 8 HX repeats [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This patient\u0026rsquo;s mutation represents an in-frame duplication of six nucleotides resulting in the insertion of an additional leucine-histidine dipeptide between residues 1063 and 1064. Although the protein remains full-length and the reading frame is preserved, any disruption of the periodic HX motif is believed to underlie the pathogenesis of most cases of ATN1-related neurodevelopmental disorder (ATN1-NDD) localized to this 16-residue segment, as seen in previously reported cases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe diagnosis of this patient with ATN1-NDD is distinct for several reasons. As a relatively recently described rare disease, the diagnosis and reporting of new patients has largely been confined to pediatric patients with profound developmental/intellectual delays and symptoms typical of the CHEDDA diagnostic term [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Comparatively, while the patient did present with oral intolerance, microcephaly, and intellectual and developmental delays, the patient is notable for having only mild intellectual disability where he was able to work in a retail store and attend school in a supported capacity. Only one other patient reported was determined to have a mild delay, with all other patients being found to have profound delays [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In addition, he lacked the reported hypotonia and more severe digit abnormalities specific to the CHEDDA designation as well as other commonly seen symptoms including congenital malformations, hearing loss, or respiratory symptoms [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Most significantly, he is the oldest reported patient receiving this diagnosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. There is little information about the life span of patients with this disease as it was first reported in 2019 and most of the patients now recently diagnosed have been pediatric patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This patient who recently turned 30 and presented in relatively good physical health does provide a potential clue into life expectancies of individuals with this disease. However, the generalization of this case to other patients with CHEDDA is limited by the fact that this patient has had a milder disease course since birth. In addition, reports of worsening memory retention in our patient may indicate eventual disease progression and warrants further follow-up and evaluation to better understand the long-term clinical course of CHEDDA.\u003c/p\u003e\u003cp\u003eMost mutations have been determined to be de novo mutations in this highly conserved region, consistent with broader findings in adult-onset mendelian disease cohorts where de novo mutations account for over 60% of autosomal dominant diagnoses [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Interestingly, the only other patient who was noted to have only mild developmental delay regarding both fine and gross motor skills and no hypotonia was found to also have a duplication of the amino acids: histidine and leucine in the HX motif rather than the more typically seen type of mutation of indels or single-nucleotide variants. This genotype is similar to our patient described where instead of an insertion or deletion of random sequences, there is a tandem duplication of the motif with a preserved reading frame [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This case represents only the second reported patient with this unique genotype and a similarly mild presentation. These genotypes may help explain why some individuals with this disease present with milder symptoms, potentially representing a larger population that remains undiagnosed [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWhile our patient is the first adult patient to be recognized with this rare disease, it has been thought that there are likely more patients with more mild developmental disease similar to our patient who have lived into adulthood [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. As we were able to diagnose our patient with this disease through new updates in exome sequencing and variant identification, this gives further support to the importance of variant reclassification and patient follow up through time to determine if any new findings have been reported which could explain their symptoms. In a recent study using genome sequencing after a negative diagnostic evaluation, over half of patients (53.4%) who received a molecular diagnosis could have received the same diagnosis through re-analysis of prior exome-sequencing [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This re-analysis utilizes advances and discoveries in gene-disease relationships further supporting ongoing follow-up of patients with symptoms of unidentified etiologies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights a uniquely mild and adult presentation of ATN1-related neurodevelopmental disorder, a rare condition typically recognized in pediatric patients with profound developmental delays and hypotonia. The patient\u0026rsquo;s genotype\u0026mdash;an in-frame tandem duplication within the HX motif\u0026mdash;mirrors the only previously reported individual with a similarly mild phenotype, suggesting a possible genotype-phenotype correlation and wider phenotypic variability within CHEDDA, which is more commonly associated with more severe indels and single-nucleotide variants. This case expands the known clinical spectrum of ATN1-NDD and underscores the importance of reclassifying genetic variants over time. It also supports the consideration of \u003cem\u003eATN1\u003c/em\u003e testing and genetic re-evaluation in adults with unexplained mild intellectual disability and other syndromic findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish:\u0026nbsp;\u003c/strong\u003eVerbal informed consent was obtained from the patient\u0026rsquo;s father after detailed explanation of the case report and its intended publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by William McGonigle, Sneha Kapil, Dayna Morel, and Deborah Barbouth. The first draft of the manuscript was written by William McGonigle and Sneha Kapil and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWhitton C, Palmer E, Alkuraya F. ATN1-Related Neurodevelopmental Disorder. In: GeneReviews\u0026reg; [Internet]. National Library of Medicine. 2022. https://www.ncbi.nlm.nih.gov/books/NBK583218/. Accessed 24 July 2025.\u003c/li\u003e\n\u003cli\u003ePalmer EE, Hong S, Al Zahrani F, Hashem MO, Aleisa FA, Ahmed HMJ, Kandula T, Macintosh R, Minoche AE, Puttick C, Gayevskiy V, Drew AP, Cowley MJ, Dinger M, Rosenfeld JA, Xiao R, Cho MT, Yakubu SF, Henderson LB, Guillen Sacoto MJ, Begtrup A, Hamad M, Shinawi M, Andrews MV, Jones MC, Lindstrom K, Bristol RE, Kayani S, Snyder M, Villanueva MM, Schteinschnaider A, Faivre L, Thauvin C, Vitobello A, Roscioli T, Kirk EP, Bye A, Merzaban J, Jaremko Ł, Jaremko M, Sachdev RK, Alkuraya FS, Arold ST. De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome. Am J Hum Genet. 2019; https://doi.org/10.1016/j.ajhg.2019.01.013. Erratum in: Am J Hum Genet. 2019; https://doi.org/10.1016/j.ajhg.2019.03.016. \u003c/li\u003e\n\u003cli\u003ePrades S, Melo de Gusmao C, Grimaldi S, Shiloh-Malawasky Y, Felton T, Houlden H. DRPLA. In: GeneReviews\u0026reg; [Internet]. National Library of Medicine.1999 [Updated 2023]; https://www.ncbi.nlm.nih.gov/books/NBK1491/. Accessed 24 July 2025.\u003c/li\u003e\n\u003cli\u003ePalmer EE, Whitton C, Hashem MO, Clark RD, Ramanathan S, Starr LJ, Velasco D, De Dios JK, Singh E, Cormier-Daire V, Chopra M, Rodan LH, Nellaker C, Lakhani S, Mallack EJ, Panzer K, Sidhu A, Wentzensen IM, Lacombe D, Michaud V, Alkuraya FS. CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum. \u003cem\u003eClin Genet\u003c/em\u003e. 2021; https://doi.org/10.1111/cge.14022 \u003c/li\u003e\n\u003cli\u003eHui, Jessica, Sedat Giray Kandemirli, and Takashi Shawn Sato. CHEDDA syndrome: A case report and review of the literature for this newly described entity. Radiology Case Reports. 2020; https://doi.org/10.1016/j.radcr.2020.05.079 \u003c/li\u003e\n\u003cli\u003eLuo S, Hu Y, Xiong P, Tan L, Zhao P, Huang Y, Xiao C, Zhu H, He X. A novel variant in the HX repeat motif of ATN1 in a Chinese patient with CHEDDA syndrome and literature review. Molecular Genetics \u0026amp; Genomic Medicine 2022; https://doi.org/10.1002/mgg3.2068. \u003c/li\u003e\n\u003cli\u003eMakarova, E., Legro, N., \u0026amp; Aliu, E. eP185: A novel, milder case of CHEDDA syndrome caused by a de novo variant outside of the canonical HX-motif of ATN1. Genetics in Medicine. 2022; https://doi.org/10.1016/j.gim.2022.01.221. \u003c/li\u003e\n\u003cli\u003eWojcik MH, Lemire G, Berger E, et al. Genome Sequencing for Diagnosing Rare Diseases. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2024; https://doi.org/10.1056/NEJMoa2314761 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"CHEDDA, ATN-1, intellectual disability, autism, HX motif, neurodevelopmental disorder","lastPublishedDoi":"10.21203/rs.3.rs-7274724/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7274724/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eATN1-related neurodevelopmental disorder (ATN1-NDD) is a rare genetic condition typically diagnosed in infancy, characterized by profound developmental delay and hypotonia due to heterozygous pathogenic variants in the highly conserved HX motif of the \u003cem\u003eATN1\u003c/em\u003e gene. We present a unique case of a 29-year-old male with mild intellectual disability, autism spectrum disorder, and microcephaly, diagnosed in adulthood through reclassification of a heterozygous in-frame tandem duplication variant (c.3188_3193dupTGCACC) within the HX motif. This case represents one of the mildest and latest reported presentations of ATN1-NDD, expanding the known phenotypic spectrum. Notably, the patient\u0026rsquo;s genotype parallels the only other known mild case, suggesting a possible genotype-phenotype correlation distinct from the severe phenotypes typically observed. This report underscores the importance of genetic re-evaluation in adults with unexplained neurodevelopmental disorders and contributes valuable insight into the variability and natural history of ATN1-NDD.\u003c/p\u003e","manuscriptTitle":"Adult Diagnosis of ATN1-Related Neurodevelopmental Disorder: A Case Report of a Mild Phenotype with In-Frame Tandem Duplication in the HX Motif","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-14 11:23:28","doi":"10.21203/rs.3.rs-7274724/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":"4e3bbc77-f58d-4ed0-9503-3af57ec9fe8d","owner":[],"postedDate":"August 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T16:02:22+00:00","versionOfRecord":{"articleIdentity":"rs-7274724","link":"https://doi.org/10.1007/s40142-026-00245-6","journal":{"identity":"current-genetic-medicine-reports","isVorOnly":false,"title":"Current Genetic Medicine Reports"},"publishedOn":"2026-04-27 15:58:08","publishedOnDateReadable":"April 27th, 2026"},"versionCreatedAt":"2025-08-14 11:23:28","video":"","vorDoi":"10.1007/s40142-026-00245-6","vorDoiUrl":"https://doi.org/10.1007/s40142-026-00245-6","workflowStages":[]},"version":"v1","identity":"rs-7274724","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7274724","identity":"rs-7274724","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}