American Journal of Medical Genetics Part C: Seminars in Medical Genetics最新文献

{"title":"Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype","authors":"Camilla Sarli,&nbsp;Liselot van der Laan,&nbsp;Jack Reilly,&nbsp;Slavica Trajkova,&nbsp;Diana Carli,&nbsp;Alfredo Brusco,&nbsp;Michael A. Levy,&nbsp;Raissa Relator,&nbsp;Jennifer Kerkhof,&nbsp;Haley McConkey,&nbsp;Matthew L. Tedder,&nbsp;Cindy Skinner,&nbsp;Mariëlle Alders,&nbsp;Peter Henneman,&nbsp;Raoul C. M. Hennekam,&nbsp;Claudia Ciaccio,&nbsp;Stefano D'Arrigo,&nbsp;Antonio Vitobello,&nbsp;Laurence Faivre,&nbsp;Sacha Weber,&nbsp;Aline Vincent-Devulder,&nbsp;Laurence Perrin,&nbsp;Alexia Bourgois,&nbsp;Toshiyuki Yamamoto,&nbsp;Kay Metcalfe,&nbsp;Marcella Zollino,&nbsp;Usha Kini,&nbsp;Daniela Oliveira,&nbsp;Sergio B. Sousa,&nbsp;Denise Williams,&nbsp;Gerarda Cappuccio,&nbsp;Bekim Sadikovic,&nbsp;Nicola Brunetti-Pierri","doi":"10.1002/ajmg.c.32089","DOIUrl":"10.1002/ajmg.c.32089","url":null,"abstract":"<p>Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome that presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability. BIS is caused by pathogenic variants in <i>SMARCA2</i>, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation. Individuals bearing variants within the bipartite nuclear localization (BNL) signal domain of <i>ADNP</i> present with the neurodevelopmental disorder known as Helsmoortel-Van Der Aa Syndrome (HVDAS). Distinct DNA methylation profiles referred to as episignatures have been reported in HVDAS and BAF complex disorders. Due to molecular interactions between <i>ADNP</i> and BAF complex, and an overlapping craniofacial phenotype with narrowing of the palpebral fissures in a subset of patients with HVDAS and BIS, we hypothesized the possibility of a common phenotype-specific episignature. A distinct episignature was shared by 15 individuals with BIS-causing <i>SMARCA2</i> pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic <i>ADNP</i> variants. This represents first evidence of a sensitive phenotype-specific episignature biomarker shared across distinct genetic conditions that also exhibit unique gene-specific episignatures.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"196 4","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simpson–Golabi–Behmel syndrome","authors":"Alessandro Vaisfeld,&nbsp;Giovanni Neri","doi":"10.1002/ajmg.c.32088","DOIUrl":"10.1002/ajmg.c.32088","url":null,"abstract":"<p>The Simpson–Golabi–Behmel syndrome (SGBS; OMIM 312870) is an overgrowth/multiple congenital anomalies/dysplasia condition, inherited as an X-linked semi-dominant trait, with variable expressivity in males and reduced penetrance and expressivity in females. The clinical spectrum is broad, ranging from mild manifestations in both males and females to multiple malformations and neonatal death in the more severely affected cases. An increased risk of neoplasia is reported, requiring periodical surveillance. Intellectual development is normal in most cases. SGBS is caused by a loss-of-function mutation of the <i>GPC3</i> gene, either deletions or point mutations, distributed all over the gene. Notably, <i>GPC3</i> deletion/point mutations are not found in a significant proportion of clinically diagnosed SGBS cases. The protein product GPC3 is a glypican functioning as a receptor for Hh at the cell surface, involved in the Hh-Ptc-Smo signaling pathway, a regulator of cellular growth.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"196 4","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigations of an individual with a Marfanoid habitus, mild intellectual disability, and severe social anxiety identifies PCDHGA5 as a candidate neurodevelopmental disorder gene","authors":"Henri Margot,&nbsp;Adrien Pizano,&nbsp;Anouck Amestoy,&nbsp;Didier Lacombe,&nbsp;Camille Berges,&nbsp;Claire Beneteau,&nbsp;A. Micheil Innes","doi":"10.1002/ajmg.c.32087","DOIUrl":"10.1002/ajmg.c.32087","url":null,"abstract":"<p>Marfanoid habitus and intellectual disability (MHID) co-occur in multiple neurodevelopmental disorders (NDD). Among those, Lujan-Fryns, an X-linked genetic disorder associated with variants in <i>MED12</i> was the first such syndrome identified. Accurate molecular diagnosis for these MHID syndromes remains a challenge due to significant clinical and genetic heterogeneity. We present a case report of a 20-year-old male patient with MHID and severe social anxiety. A comprehensive clinical evaluation, including morphotype assessment, cognitive, and psychometric and genetic testing, was conducted to provide a detailed understanding of the patient's complex clinical presentation. Psychometric assessments revealed severe social anxiety and various cognitive and emotional challenges. Despite some autism-like symptoms, the patient's clinical presentation was more aligned with mild intellectual disability. Exome sequencing was inconclusive but identified a heterozygous de novo missense variant in the <i>PCDHGA5</i> gene. This gene is not known in human pathology yet, but we also report a second patient with a syndromic neurodevelopmental disorder and a rare de novo variant which leads us to propose this as a candidate gene. Our findings emphasize the importance of multidisciplinary approach in the diagnosis and management of MHID. This case report underscores the need for objective clinical evaluations and standardized tools to better understand the complex clinical profiles of patients with NDDs. The identification of novel <i>PCDHGA5</i> gene variants adds this gene's candidacy to the genetic landscape of MHID-NDD, warranting further investigation to determine its potential contribution.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"196 4","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140583215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dream of a diagnosis","authors":"Golda Grinberg","doi":"10.1002/ajmg.c.32086","DOIUrl":"10.1002/ajmg.c.32086","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"196 2-3","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140583210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Domain-specific phenotypes in LINS1-related disorder—A Chinese family with the Q92X variant and literature review","authors":"Xu-Ying Li,&nbsp;Zhanjun Wang,&nbsp;Yanping Yang,&nbsp;Ruichai Lin,&nbsp;Chaodong Wang","doi":"10.1002/ajmg.c.32085","DOIUrl":"10.1002/ajmg.c.32085","url":null,"abstract":"<p><i>LINS1</i> is the human homolog of the Drosophila segment polarity gene that encodes an essential regulator of the wingless/Wnt signaling. By 2011, only seven pedigrees (16 patients) with eight causative variants in <i>LINS1</i> gene have been reported. These cases mainly presented with infancy-/child-onset neurodevelopmental disorders, facial dysmorphia, and other clinical features, and a wide spectrum of clinically distinct phenotypes were also manifested. In our study, two brothers in a family were admitted and diagnosed with child-onset movement disorders, slight intellectual disability, psychological symptoms, eye problems, urinary and bowel dysfunction, mitral value prolapse, and Q-T prolongation. By exome sequencing, we identified a nonsense homozygous pathogenic variant (<i>LINS1</i>: c.274C &gt; T (p.Q92X)), which had been reported in a case diagnosed with intellectual disability and psychiatric disorders (such as schizophrenia and anxiety). Compared with this case, the clinical features of our cases were distinct. In particular, our cases displayed unusual features of heart and blood system. Furthermore, the genotype–phenotype relationship analysis suggested that distinct phenotypes presented in cases carrying variants in different domains of the <i>LINS1</i> gene. In conclusions, our findings suggest the high clinical variations in the <i>LINS1</i> variants-related disorders. Moreover, the Q92X might be a recurrent variant in Hans of Southern China.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"196 4","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 196, Number 1, March 2024","authors":"","doi":"10.1002/ajmg.c.32084","DOIUrl":"https://doi.org/10.1002/ajmg.c.32084","url":null,"abstract":"<p><b>Cover legend: Photo credit: Andy Meredith, man with Down syndrome. Andy Meredith Photography,</b> https://andymeredith.com\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"196 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140104495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Table of Contents, Volume 196, Number 1, March 2024","authors":"","doi":"10.1002/ajmg.c.32047","DOIUrl":"https://doi.org/10.1002/ajmg.c.32047","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"196 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140104466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An extra X chromosome among adult women in the Million Veteran Program: A more benign perspective of trisomy X.","authors":"Shanlee M Davis, Craig C Teerlink, Julie A Lynch, Natalia Klamut, Bryan R Gorman, Meghana S Pagadala, Matthew S Panizzon, Victoria C Merritt, Giulio Genovese, Judith L Ross, Richard L Hauger","doi":"10.1002/ajmg.c.32083","DOIUrl":"10.1002/ajmg.c.32083","url":null,"abstract":"<p><p>Despite affecting in 1 in every 1000 females, remarkably little is known about trisomy X syndrome (47,XXX), especially among older adults who are undiagnosed. In this study, we aimed to determine the prevalence of 47,XXX among females enrolled in the Million Veterans Program (MVP; mean age 50.2 ± 13.6 years), and compare broad health outcomes between females with 47,XXX and 46,XX matched controls. We identified 61 females with an additional X chromosome, corresponding to a prevalence of 103 per 100,000 females; 27.9% had been clinically diagnosed. Females with 47,XXX had taller stature (+6.1 cm, p < 0.001), greater rate of outpatient encounters (p = 0.026), higher odds of kidney disease (odds ratio [OR] = 12.3; 95% confidence interval [CI] 2.9-51.8), glaucoma (OR = 5.1; 95% CI 1.5-13.9), and congestive heart failure (OR = 5.6; 95% CI 1.4-24.2), and were more likely to be unemployed (p = 0.008) with lower annual income (p = 0.021) when compared with 46,XX controls of the same age and genetic ancestry. However, there were no differences in the rates of other encounter types, Charlson Comorbidity Index, all other medical and psychological diagnoses, military service history or quality of life metrics. In conclusion, in this aging and predominately undiagnosed sample, 47,XXX conferred few differences when compared with matched controls, offering a more reassuring perspective to the trisomy X literature.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"e32083"},"PeriodicalIF":2.8,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The National Institutes of Health INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project: Accelerating research discoveries for people with Down syndrome across the lifespan","authors":"Sujata Bardhan,&nbsp;Huiqing Li,&nbsp;Erika Tarver,&nbsp;Charlene Schramm,&nbsp;Marishka Brown,&nbsp;Linda Garcia,&nbsp;Bryanna Schwartz,&nbsp;Anna Mazzucco,&nbsp;Nikila Natarajan,&nbsp;Elizabeth Walsh,&nbsp;Laurie Ryan,&nbsp;Gail Pearson,&nbsp;Melissa A. Parisi","doi":"10.1002/ajmg.c.32081","DOIUrl":"10.1002/ajmg.c.32081","url":null,"abstract":"<p>The National Institutes of Health (NIH) has a long-standing history of support for research in Down syndrome (DS). In response to a 2018 congressional directive for a trans-NIH initiative to address medical issues in DS, NIH launched the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). Reflecting the three INCLUDE components of basic science research, cohort development, and clinical trials, the Project has published funding opportunities to address conditions such as immune disorders and Alzheimer's disease. Due to a steady expansion in dedicated funding over its first 5 years, INCLUDE has invested $258 M in over 250 new research projects. INCLUDE also supports training initiatives to expand the number and diversity of investigators studying DS. NIH has funded an INCLUDE Data Coordinating Center that is collecting de-identified clinical information and multi-omics data from research participants for broad data sharing and secondary analyses. Through the DS-Connect® registry, INCLUDE investigators can access recruitment support. The INCLUDE Research Plan articulates research goals for the program, with an emphasis on diversity of research participants and investigators. Finally, a new Cohort Development Program is poised to increase the impact of the INCLUDE Project by recruiting a large DS cohort across the lifespan.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"196 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 193, Number 4, December 2023","authors":"","doi":"10.1002/ajmg.c.31985","DOIUrl":"10.1002/ajmg.c.31985","url":null,"abstract":"<p><b>Cover legend: Photo credit: Kunal Sharma, a talented photographer with Down syndrome. His website is</b> kunalsklicks.com\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 4","pages":""},"PeriodicalIF":2.8,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.31985","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139068982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}