American Journal of Medical Genetics Part A最新文献_第9页

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-05 DOI: 10.1002/ajmg.a.64192

Alexandra Garrett, Vera M Kalscheuer, Rebeca Ridings Figueroa, Elizabeth E Palmer, Angela T Morgan

{"title":"CLCN4-Related Neurodevelopmental Condition: Characterization of Speech and Language Abilities.","authors":"Alexandra Garrett, Vera M Kalscheuer, Rebeca Ridings Figueroa, Elizabeth E Palmer, Angela T Morgan","doi":"10.1002/ajmg.a.64192","DOIUrl":"https://doi.org/10.1002/ajmg.a.64192","url":null,"abstract":"Speech and language difficulties are a core feature of the CLCN4-related neurodevelopmental condition, but these have not been well described. Here we systematically phenotype speech and language in 13 participants (10 female, aged 1 year 10 months-41 years 10 months) with pathogenic CLCN4 variants (12 missense de novo, 1 premature stop codon maternal inheritance). Speech, language, and augmentative and alternative communication (AAC) methods were examined. Expressive and receptive language conditions were highly penetrant (12/13, 92%). Eight participants were minimally verbal but used a range of low (e.g., gesture) and high-tech (e.g., device) methods to communicate. Verbal participants had both apraxia and dysarthria, characterized by inconsistent productions, sound distortions, resonance changes, and persistent voice quality and prosodic errors. Participants were all intentional communicators, being motivated to get their message across. A discrepancy was present, however, between the ability to express basic needs versus demonstrate social skills or social exchanges. Data highlight the potential for the implementation of tailored AAC to enhance functional social participation and extend language abilities. Communication difficulties are pervasive in CLCN4-related neurodevelopmental condition. Data emphasize the importance of individualized and timely speech therapy, and particularly the introduction of AAC to optimize language growth.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64192"},"PeriodicalIF":1.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Blended Phenotypes in Individuals With Rare Diseases: A Brazilian Case Series. 罕见疾病患者的混合表型：巴西病例系列。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-05 DOI: 10.1002/ajmg.a.64209

Caroline Brandão Piai, Gabriela Yumi Goto Salti, Marcella Cardoso Allegro, Priscila Barbosa Betty, Fernanda de Souza Valente, Isabela Dorneles Pasa, Bruno de Oliveira Stephan, Bianca Domit Werner Linnenkamp, Rachel Sayuri Honjo, Debora Romeo Bertola, Masamune Sakamoto, Yuta Inoue, Ken Saida, Naomi Tsuchida, Noriko Miyake, Naomichi Matsumoto, Chong Ae Kim

{"title":"Blended Phenotypes in Individuals With Rare Diseases: A Brazilian Case Series.","authors":"Caroline Brandão Piai, Gabriela Yumi Goto Salti, Marcella Cardoso Allegro, Priscila Barbosa Betty, Fernanda de Souza Valente, Isabela Dorneles Pasa, Bruno de Oliveira Stephan, Bianca Domit Werner Linnenkamp, Rachel Sayuri Honjo, Debora Romeo Bertola, Masamune Sakamoto, Yuta Inoue, Ken Saida, Naomi Tsuchida, Noriko Miyake, Naomichi Matsumoto, Chong Ae Kim","doi":"10.1002/ajmg.a.64209","DOIUrl":"https://doi.org/10.1002/ajmg.a.64209","url":null,"abstract":"The growing use of whole exome sequencing and whole genome sequencing in clinical practice has revealed the existence of a group of individuals that do not fit into only one molecular diagnosis. These subjects are those in whom pathogenic or likely pathogenic variants occur in more than one gene, creating \"blended phenotypes\" There are also genes that warrant reporting, even if they are not associated with the primary phenotype, referred to as 'secondary findings'. In this report, we analyze the prevalence of blended phenotypes in a cohort of 447 individuals who underwent broad genomic sequencing and also present a case series of eight probands who presented multiple diagnoses, generating a mixed phenotype and creating a peculiar clinical situation. In total, 3.86% (8/207) were found to have blended phenotypes, which would have been missed had those individuals not undergone comprehensive genetic testing. We reflect upon the clinical complexity of such cases and explore the consequences of the use of broad sequencing strategies in clinical practice, particularly focusing on the potential to provide a more complete diagnostic scenario. By acknowledging and understanding the complexities of blended phenotypes, clinicians can adopt a more nuanced and tailored approach to patient care.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64209"},"PeriodicalIF":1.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Secondary Findings in a Research Cohort: Spectrum and the Indian Perspective. 研究队列的次要发现：光谱和印度人的观点。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-05 DOI: 10.1002/ajmg.a.64199

Pooja Motwani, Rajesh K Maurya, Dhwoni, Shubha R Phadke, Amita Moirangthem

{"title":"Secondary Findings in a Research Cohort: Spectrum and the Indian Perspective.","authors":"Pooja Motwani, Rajesh K Maurya, Dhwoni, Shubha R Phadke, Amita Moirangthem","doi":"10.1002/ajmg.a.64199","DOIUrl":"https://doi.org/10.1002/ajmg.a.64199","url":null,"abstract":"Genomic sequencing identifies both primary findings related to a patient's phenotype and secondary findings (SFs) which are actionable with early intervention. In the Indian population, there is limited data about types and frequencies of SFs as well as on the understanding of patients' perspectives on receiving these findings. We identified P/LP variants in SF genes (ACMG v3.2) from 500 families who underwent research-based exome sequencing at our center. Families were recontacted, and phenotypic diagnostic tests were done for at-risk individuals. In a separate group of families undergoing diagnostic exome sequencing, a questionnaire-based survey assessed parents' perspectives of these findings for themselves and their extended family members. Frequency of SF is 2.2% with 12 P/LP variants identified in 11 families predominantly in genes of the cardiovascular group (6) and cancer group (5). One family had a positive family history compatible with the associated disease. In response to the questionnaire survey of families undergoing diagnostic exome sequencing, the majority of parents supported SF inclusion in proband tests (97.2%) and in themselves (84.7%). While thorough knowledge of all SFs was favored, financial constraints reduced willingness to pay for additional tests. A comprehensive study from Medical Genetics Center in India reporting 2.2% frequency of SF in 81 SF genes. Clinicians should ensure thorough pretest counseling and clear communication on long-term follow-up for phenotype-negative individuals, variable penetrance, expressivity, and differential severity of SFs and stringent variant interpretation. With the surge in genomic diagnostic tests, it is imperative to assess preparedness of the healthcare systems to ensure equitable and sustainable care for all patients.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64199"},"PeriodicalIF":1.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A New Case Linking a Somatic NRAS Variant to Encephalocraniocutaneous Lipomatosis. 一个将体细胞NRAS变异与脑颅皮脂肪病联系起来的新病例。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-01 DOI: 10.1002/ajmg.a.64202

Omar Azrak, Sheng-Che Hung, Nathaniel G Wooten, Clara C Hildebrandt

引用次数: 0

Medical Multimorbidity in Patients With Treatment-Resistant Psychosis and Rare Copy Number Variants: A Retrospective Case Series of 24 Patients. 难治性精神病和罕见拷贝数变异患者的医学多病：24例回顾性病例系列

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-01 DOI: 10.1002/ajmg.a.64215

Tyler E Dietterich, Rose Mary Xavier, Maya L Lichtenstein, Matthew K Harner, Lisa Bruno, Robert Stowe, Martilias Farrell, Rita A Shaughnessy, Jonathan S Berg, Patrick F Sullivan, Richard C Josiassen

{"title":"Medical Multimorbidity in Patients With Treatment-Resistant Psychosis and Rare Copy Number Variants: A Retrospective Case Series of 24 Patients.","authors":"Tyler E Dietterich, Rose Mary Xavier, Maya L Lichtenstein, Matthew K Harner, Lisa Bruno, Robert Stowe, Martilias Farrell, Rita A Shaughnessy, Jonathan S Berg, Patrick F Sullivan, Richard C Josiassen","doi":"10.1002/ajmg.a.64215","DOIUrl":"10.1002/ajmg.a.64215","url":null,"abstract":"Neurodevelopmental disorder-risk copy number variations (NDD CNVs) are associated with complex neuropsychiatric phenotypes. These CNVs also confer risk for a host of medical outcomes in adults; yet, the long-term health consequences in the context of comorbid psychiatric illness have not been well documented. Twenty-four psychiatric inpatients with treatment-resistant psychosis were identified as carriers of NDD CNVs as part of a larger Pennsylvania State Hospital genomics study. Comprehensive life course phenotyping was performed through review of medical records, specialized neurobehavioral evaluation, and synthesis of data using the Human Phenotype Ontology. Phenotypes examined across the cohort indicated comorbid medical manifestations across multiple organ systems. Cardiovascular disorders were present in 96% of patients and motor disorders in 92%. All patients had multiple organ system involvement, and most organ systems (12/17 systems) were affected in 50% or more of patients, culminating in a high degree of individual-level multimorbidity. Comparing our observations to previously known CNV-associated phenotypes indicated several potentially novel health outcomes for individual CNV loci. Our descriptive case series supports a complex and multidimensional course of illness. Thorough reporting on the long-term implications of these variants is the first step toward advancing clinical care for these complex psychiatric patients carrying NDD CNVs.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64215"},"PeriodicalIF":1.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Joubert Syndrome in Children-A Comprehensive Analysis of Quality of Life, Functional Independence and Family Impact. 儿童Joubert综合征——生活质量、功能独立性和家庭影响的综合分析。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-01 DOI: 10.1002/ajmg.a.64213

Erhan Elmaoğlu, Adnan Batuhan Coşkun, Serkan Usgu, Zerrin Çiğdem, Selda Yüzer Alsaç

{"title":"Joubert Syndrome in Children-A Comprehensive Analysis of Quality of Life, Functional Independence and Family Impact.","authors":"Erhan Elmaoğlu, Adnan Batuhan Coşkun, Serkan Usgu, Zerrin Çiğdem, Selda Yüzer Alsaç","doi":"10.1002/ajmg.a.64213","DOIUrl":"https://doi.org/10.1002/ajmg.a.64213","url":null,"abstract":"This study examines the quality of life, functional independence, and family impact of children diagnosed with Joubert Syndrome (JS) to address gaps in the literature on its developmental and psychosocial challenges. A descriptive, cross-sectional study was conducted with 49 parents of children with JS in Turkey. Data were collected using the Pediatric Quality of Life Inventory, Pediatric Functional Independence Measure, and Impact on Family Scale. Statistical analyses included descriptive and reliability assessments. Children with JS exhibited significant motor and cognitive delays, reduced functional independence, and lower quality of life. Feeding difficulties affected 38.8% of participants, highlighting the need for early nutritional interventions. Consanguineous marriage was reported by 61.2% of families, yet only 8.2% underwent genetic screening, emphasizing the importance of genetic counseling. Parents faced high psychosocial and economic burdens, underscoring the need for structured family support programs. The findings highlight the need for early, multidisciplinary interventions, including physical and speech therapy, nutritional support, and psychosocial care, to enhance functional independence and overall well-being. A comprehensive care model integrating neurology, pulmonology, rehabilitation, and genetic counseling is essential for improving outcomes in JS. A family-centered, multidisciplinary approach should be prioritized to improve patient care and caregiver support. Expanding rehabilitation services, genetic counseling, and structured family education can enhance long-term quality of life and independence in children with JS.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64213"},"PeriodicalIF":1.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of a Second-Hit Brain Somatic DEPDC5 Variant Supports Causality of a DEPDC5 Germline Variant of Uncertain Significance. Time for a Classification Update? 二击脑体细胞DEPDC5变异的鉴定支持了不确定意义的DEPDC5种系变异的因果关系。是时候更新分类了？

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-31 DOI: 10.1002/ajmg.a.64204

Ala'a Alsayed, Zainab Hakim, Daria Merrikh, Maryam Khanbabaei, Navprabhjot Kaur, Walter Hader, Tyler Soule, Setareh Ashtiani, Grace Polanco-Tovar, Morris Scantlebury, Hamed Rahi, Yang Cao, Jennifer A Chan, Juan P Appendino, Gerald Pfeffer, Ping Yee Billie Au, Karl Martin Klein

{"title":"Identification of a Second-Hit Brain Somatic DEPDC5 Variant Supports Causality of a DEPDC5 Germline Variant of Uncertain Significance. Time for a Classification Update?","authors":"Ala'a Alsayed, Zainab Hakim, Daria Merrikh, Maryam Khanbabaei, Navprabhjot Kaur, Walter Hader, Tyler Soule, Setareh Ashtiani, Grace Polanco-Tovar, Morris Scantlebury, Hamed Rahi, Yang Cao, Jennifer A Chan, Juan P Appendino, Gerald Pfeffer, Ping Yee Billie Au, Karl Martin Klein","doi":"10.1002/ajmg.a.64204","DOIUrl":"https://doi.org/10.1002/ajmg.a.64204","url":null,"abstract":"Germline variants in DEPDC5 are a cause of familial focal epilepsy with variable foci. Affected individuals may have focal cortical dysplasia if a second brain somatic variant occurs. As access to brain tissue is limited, the second somatic hit in the brain is usually presumed if a clear pathogenic germline variant is present. Here, we present a patient with structural focal epilepsy due to focal cortical dysplasia. He underwent epilepsy surgery at age 2 months. Clinical genetic testing revealed a germline variant of uncertain significance (VUS) DEPDC5 c.920T>G, p. (Leu307Arg). We hypothesized that if the proband's germline DEPDC5 variant was disease-causal, a second somatic variant may be identifiable in affected cortical tissue. DNA was extracted from archived brain formalin-fixed paraffin-embedded tissue and subjected to deep gene panel analysis. This revealed an additional somatic pathogenic variant in DEPDC5, which was confirmed using droplet digital PCR. Identification of the second somatic hit in brain tissue (DEPDC5 c.982C>T, p.(Arg328*)) confirmed the two-hit situation in this patient and supported disease causality of the germline variant. In conclusion, testing tissue for somatic variants may be clinically relevant at a patient-specific level if a germline VUS affects a gene where a two-hit mechanism is known.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64204"},"PeriodicalIF":1.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ARSK-Related Mucopolysaccharidosis Type 10. arsk相关粘多糖病10型。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-31 DOI: 10.1002/ajmg.a.64210

Intisar Al Fahdi, Swati Singh, Krishnaveni Yadavalli, Kiranam Chatti, Gandham SriLakshmi Bhavani, Katta M Girisha

引用次数: 0

Further Evidence That Chondrocalcinosis 1 (CCAL1) is a Confirmed Mendelian Phenotype With a Known Molecular Basis. 软骨钙化1 （CCAL1）是一种已知分子基础的孟德尔表型的进一步证据。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-30 DOI: 10.1002/ajmg.a.64185

Anna-Christina Pansa, Mareike Selig, Markus Wingendorf, Matthew A Brown, Oliver Bartsch

{"title":"Further Evidence That Chondrocalcinosis 1 (CCAL1) is a Confirmed Mendelian Phenotype With a Known Molecular Basis.","authors":"Anna-Christina Pansa, Mareike Selig, Markus Wingendorf, Matthew A Brown, Oliver Bartsch","doi":"10.1002/ajmg.a.64185","DOIUrl":"https://doi.org/10.1002/ajmg.a.64185","url":null,"abstract":"Chondrocalcinosis (CCAL), also known as calcium pyrophosphate dihydrate deposition disease (CPPDD), is a frequent multifactorial condition in the elderly, but there are two rare autosomal dominant Mendelian forms, CCAL1 (OMIM %600668) and CCAL2. Only three families with molecularly proven CCAL1 have been reported. Here, we describe an additional family from Germany (12 individuals, nine living) with CPPDD manifesting in the third decade of life, presenting with severe spinal problems and variable levels of disability, only two of them with hip problems. The mildly impaired growth in this family (median height at age 20: 10th percentile) may represent an as yet undescribed sign of CCAL1, or alternatively familial short stature. In all documented families and in this family, the disorder resulted from the recurrent heterozygous stop-loss variant NM_002546.4:c.1205A>T; p.(Ter402Leuext*19) in TNFRSB11B on chromosome 8q24, which predicts an extended osteoprotegerin protein with 19 additional amino acid residues. The pathomechanism of CCAL1 is not known. Biallelic TNFRSF11B loss-of-function variants cause autosomal recessive juvenile Paget's disease of bone (PDB5); shared features between CCAL1 and PDB5 include demineralization, osteoporosis, increased fractures, and a progressive height loss with age, but PDB5 and CCAL1 have very different phenotypes and heterozygous carriers of PDB5-associated variants are asymptomatic. Summing up, NM_002546.4:c.1205A>T represents a rare type of stop-lost variant, likely a gain-of-function variant, and to date no other variant is known to cause CCAL1. Our findings expand the phenotypic spectrum of CCAL1 and underscore that CCAL1 is a distinct rare Mendelian disorder for which the underlying molecular basis is now known.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64185"},"PeriodicalIF":1.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

45th Annual David Smith Workshop on Malformations and Morphogenesis. 第45届大卫·史密斯畸形和形态发生研讨会。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-30 DOI: 10.1002/ajmg.a.64194

Alison M Elliott, A Micheil Innes

引用次数: 0