American Journal of Medical Genetics Part A最新文献

{"title":"Diverse clinical presentation of SPTBN1 variants: Complex versus primary attention-deficit/hyperactivity disorder.","authors":"Mia O'Connell, Elizabeth Harstad, Jennifer Aites, Katheryn Hayes, Anne B Arnett, Julia Scotellaro, Soleha Patel, Stephanie J Brewster, William Barbaresi, Ryan N Doan","doi":"10.1002/ajmg.a.63851","DOIUrl":"https://doi.org/10.1002/ajmg.a.63851","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) belongs to a phenotypically broad class of mental health disorders impacting social and cognitive functioning. Despite heritability estimates of 77%-88% and a global prevalence of up to 1 in 20 children, most of the underlying genetic etiology of the disorder remains undiscovered, making it challenging to obtain a clinical molecular genetic diagnosis and to develop new treatments (Biological Psychiatry, 2005, 57, 1313; Psychological Bulletin, 2009, 135, 608; Psychological Medicine, 2014, 44, 2223). Here we report the identification of a novel ultra-rare heterozygous loss-of-function (p.Q1625*) variant in a child with complex ADHD (i.e., comorbid mild intellectual disability [ID]) and a missense (p.G1748R) variant (allele frequency of 4.7 × 10^-5) in a child with primary ADHD (i.e., absence of comorbid autism spectrum disorder [ASD], ID, or syndromic features) both in the SPTBN1 gene. Missense variants in SPTBN1 have been reported in individuals with developmental disorders, language and communication disorders, and motor delays in recent publications (Nature Genetics, 2021, 53, 1006; American Journal of Medical Genetics Part A, 2021, 185, 2037) and ClinVar, though most variants in ClinVar have uncertain disease associations. The functional impact of these 135 variants, including from the current study, were further assessed using prediction scores from the recently developed AlphaMissense tool and benchmarked against published functional studies on a subset of the variants. While heterozygous SPTBN1 variants have recently been associated with neurodevelopmental disorders characterized by global developmental delay, intellectual disability, and behavioral abnormalities, the two patients in the current study expand the phenotypic spectrum to include ADHD in the absence of more severe neurodevelopmental disorders, such as ASD and moderate to severe ID. Furthermore, the culmination of these data with existing reported cases suggests that variation including loss of function and missense events underlie a broader clinical spectrum than previously understood.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003381","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}

{"title":"Aberrant behavior checklist in youth with Prader-Willi syndrome: Preliminary study of cross-sectional and longitudinal behavior characterization.","authors":"Soo-Jeong Kim, Lydia Kim, Waylon Howard, Bridget McNulty, Parisa Salehi","doi":"10.1002/ajmg.a.63853","DOIUrl":"https://doi.org/10.1002/ajmg.a.63853","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of paternal genes on chromosome 15. The Aberrant Behavior Checklist (ABC) is a standardized rating scale for assessing problematic behaviors in persons with developmental disabilities. Our study aims to describe ABC scores in youth with PWS and track their change over time. The analysis included 69 patients. Mean ABC scores were compared in four age groups (5-8, 9-12, 13-16, and 17-22 years). A statistically significant difference was found only in the Irritability subscale, with lower scores in the 5-8 age group compared to the 9-12 age group. For change over time, scores for Irritability, Lethargy, Stereotypic Behavior, Hyperactivity subscales, and Total score were likely to decrease after age 12. Irritability subscale scores of males were predicted to increase more than those of females between ages of 5 and 12 . The Lethargy score in the nondeletion group had a greater reduction than the deletion group in the 12-20 year range. This study highlights the need for systematic collection and characterization of behavioral data given the burden of maladaptive behaviors that often persist for a lifetime.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003358","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}

{"title":"Further evidence for an attenuated phenotype of in-frame DMD deletions affecting the central rod domain of dystrophin around exon 48.","authors":"Olga Bürger, Angelika Humbel, Ivan Ivanovski, Alessandra Baumer, Anita Rauch","doi":"10.1002/ajmg.a.63842","DOIUrl":"https://doi.org/10.1002/ajmg.a.63842","url":null,"abstract":"<p><p>Alterations in the X-linked recessive DMD gene cause dystrophinopathies with a broad clinical spectrum most commonly ranging from Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to cardiomyopathy or intellectual disability. Carrier females are commonly unaffected but may show signs of dystrophinopathies. In addition, few asymptomatic male carriers with elevated creatine kinase levels have been described possibly related to deletions around exon 48. We now further support this assumed genotype-phenotype correlation by reporting an attenuated phenotype in a three-generation family with a deletion of exon 48 of the DMD gene with clinically unaffected carrier males and females. We confirmed deep intronic breakpoints in this family by genome sequencing, but such data are not available for published cases. Therefore, further observations are needed to clarify genotype-phenotype correlation in this region, since few reports also describe predicted in-frame copy number changes affecting this region in association with classical signs of dystrophinopathies.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999217","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}

{"title":"Phenotypic spectrum and tumor risk in Simpson-Golabi-Behmel syndrome: Case series and comprehensive literature review","authors":"Alex F. Nisbet,&nbsp;Aravind Viswanathan,&nbsp;Andrew M. George,&nbsp;Pedro Arias,&nbsp;Steven D. Klein,&nbsp;Julian Nevado,&nbsp;Alejandro Parra,&nbsp;Patricia Pascual,&nbsp;Dominic J. Romeo,&nbsp;Jair Tenorio-Castaño,&nbsp;Jesse A. Taylor,&nbsp;Elaine H. Zackai,&nbsp;Pablo Lapunzina,&nbsp;Jennifer M. Kalish","doi":"10.1002/ajmg.a.63840","DOIUrl":"10.1002/ajmg.a.63840","url":null,"abstract":"<p>Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the <i>GPC3</i> gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population. In addition, we discuss the phenotypic overlap between SGBS and Beckwith-Wiedemann Spectrum.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Double somatic mosaicism in Marfan syndrome","authors":"Ignacio Arroyo Carrera,&nbsp;Almudena Amor-Salamanca,&nbsp;Elena Márquez Isidro,&nbsp;Marlene Pérez-Barbeito,&nbsp;Ana Raquel Barrio Sacristán,&nbsp;Juan Pablo Ochoa","doi":"10.1002/ajmg.a.63831","DOIUrl":"10.1002/ajmg.a.63831","url":null,"abstract":"<p>Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder with great clinical variability. It is caused by heterozygous pathogenic variants in the <i>FBN1</i> gene. Cardinal manifestations involve the cardiovascular, ocular, and skeletal systems. Clinical diagnosis is based on the revised Ghent nosology. We present the case of a child with a Marfan systemic score of 9 whose genetic study revealed two pathogenic mosaic frameshift variants in the <i>FBN1</i> gene. Mosaicism is very rare in patients diagnosed with MFS, and this is the first description of a patient with two pathogenic mosaic variants in the <i>FBN1</i> gene. Both variants are present in cells derived from ectodermal (buccal swab) and mesodermal (leukocyte) tissues, suggesting a mutation prior to gastrulation. We propose a defective repair of the de novo variant in the complementary strand as the mechanism that led this individual to be a carrier of two different populations of mutant cells carrying adjacent variants.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987187","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}

{"title":"CNOT1 p.Arg535Cys variant in holoprosencephaly with late onset diabetes mellitus","authors":"Amaro Freire de Queiroz Júnior,&nbsp;Maria Teresa Vieira Sanseverino,&nbsp;Marcus Vinicius Martins Collares,&nbsp;Adriana Fornari,&nbsp;Luiza Amaral do Virmond,&nbsp;João Bosco Oliveira Filho,&nbsp;Osvaldo Artigalás,&nbsp;Têmis Maria Félix","doi":"10.1002/ajmg.a.63836","DOIUrl":"10.1002/ajmg.a.63836","url":null,"abstract":"<p>Holoprosencephaly (HPE) results from a lack of cleavage of the prosencephalon. It has a complex etiology, resulting from chromosome abnormalities or single gene variants in the Sonic hedgehog signaling pathway. A single variant, p.Arg535Cys in <i>CNOT1,</i> has been described in HPE in association with pancreatic agenesis and neonatal diabetes. Here, we report on a case of HPE and p.Arg535Cys in <i>CNOT1</i> without pancreatic agenesis where the patient presented with diabetes mellitus in adolescence. This case reinforces the role of <i>CNOT1</i> in pancreatic development. We suggest that individuals with p.Arg535Cys in <i>CNOT1</i> with no pancreas abnormalities observed at birth should be screened for diabetes during follow-up.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987186","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}

{"title":"Atypical presentation of ACCES syndrome resembling dominant Spondyloepiphyseal dysplasia tarda","authors":"Abdullah Sezer,&nbsp;Zeynep Özdemir,&nbsp;Erdem Özkan,&nbsp;Semra Çetinkaya","doi":"10.1002/ajmg.a.63852","DOIUrl":"10.1002/ajmg.a.63852","url":null,"abstract":"<p>Aplasia Cutis Congenita with Ectrodactyly Skeletal Syndrome (ACCES, OMIM #619959) is an extremely rare multiple congenital anomalies syndrome caused by haploinsufficiency of the <i>UBA2</i> gene. This syndrome presents with growth retardation, dysmorphic facial features, neurodevelopmental delay, skeletal problems including ectrodactyly, developmental dysplasia of the hip (DDH) and scoliosis, skin findings such as aplasia cutis, and some internal organ abnormalities. Our 13-year-old female patient and her 38-year-old father had a skeletal dysplasia phenotype with disproportionate short stature, bilateral DDH, mild epiphyseal involvement, scoliosis, and increased lumbar lordosis. Both were neurodevelopmentally normal and had mild dysmorphic facial features and mild ectodermal findings. The dominant inheritance pattern in the pedigree suggested a pre-diagnosis of spondyloepiphyseal dysplasia tarda. The exome sequencing analysis of the patient has identified a novel heterozygous variant, NM_005499.2:c.460-2A &gt;G, in the <i>UBA2</i> gene, and the father was found heterozygous either. The isolated spondyloepiphyseal involvement of our patients was an unusual presentation compared to patients with ACCES syndrome previously reported in the literature. Considering the highly variable expressiveness of ACCES syndrome and the co-occurrence of familial hip dysplasia and vertebral problems, we suggest that this syndrome can also be classified under “Spondyloepi(meta)physial dysplasia (SE(M)D)” in the nosology of genetic skeletal disorders.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987185","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}

{"title":"Longitudinal echocardiography in pediatric patients with hypermobile Ehlers-Danlos syndrome","authors":"Hannah Lahey,&nbsp;Haewon Shin,&nbsp;Katherine Myers,&nbsp;Kim L. McBride","doi":"10.1002/ajmg.a.63844","DOIUrl":"10.1002/ajmg.a.63844","url":null,"abstract":"<p>Vascular Ehlers-Danlos, Marfan and Loeys-Dietz syndromes have increased risk of aortic dilation and dissection. Previous early studies showed hypermobile Ehlers-Danlos syndrome (hEDS) may also have increased risk, with echocardiography screening recommended; subsequent studies have not confirmed the risk or recommended echocardiography. This pediatric-based study assessed aortic dilation prevalence in those with hEDS by serial echocardiographic examinations and assessed family history for aortic dissections. We retrospectively identified individuals with hEDS who had echocardiography studies from the electronic medical records at one pediatric center. Aortic root <i>Z</i>-scores &gt;2.0 were found in 15/225 subjects (average age 12.9 years) on initial echocardiograms, with no <i>Z</i>-score &gt;3.0. Subsequent studies (<i>n</i> = 68) found statistically significant decline in aortic root <i>Z</i>-scores. Repeat echocardiography in those with initial aortic root <i>Z</i>-score &gt;2.0 (<i>n</i> = 10) demonstrated a decline in <i>Z</i> score &lt;2.0 in seven. On final examination, 9/225 (4.0%) had a <i>Z</i>-score &gt;2.0, not statistically different from the general population. No aortic dissection occurred in first- or second-degree relatives. In conclusion, aortic root dilation rate in hEDS is likely not different from the general population. We propose that in the absence of other cardiac findings or suspicion for another disorder, echocardiography is not required in hEDS.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.63844","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regions of Homozygocity size patterns among diverse ethnic groups in Israel: Toward tailored diagnostic reporting thresholds","authors":"Idit Maya,&nbsp;Michal Levy,&nbsp;Reut Matar,&nbsp;Sarit Kahana,&nbsp;Ifaat Agmon-Fishman,&nbsp;Cochava Klein,&nbsp;Merav Gurevitch,&nbsp;Lina Basel-Salmon,&nbsp;Lena Sagi-Dain","doi":"10.1002/ajmg.a.63839","DOIUrl":"10.1002/ajmg.a.63839","url":null,"abstract":"<p>Long contiguous stretches of homozygosity or regions of homozygosity (ROH) are frequently detected via microarray and sequencing technologies. However, consensus on the establishment of specific size cutoffs for reporting ROH remains elusive. This study aims to assess the Total ROH Percentages (TRPS) and size of ROH segments across different ethnic origins, exploring potential disparities and proposing tailored diagnostic thresholds. This retrospective study included 13,035 microarray analyses conducted between 2017 to 2023. ROH segments on autosomal chromosomes were retrieved, and samples lacking ROH segments were excluded. The cohort was categorized based on reported ethnic origins, and TRPS and ROH segment size were analyzed for each origin. Distinct TRPS values were noted among different ethnic groups, ranging from median 0.36% in Ethiopian Jewish cohort and up to 6.42% in the Bedouin population. Wide range of 99th percentiles of ROH segment size for various origins was noted, ranging from 10.6 to 51.5 Mb. A significant correlation between ROH segment sizes and TRPS was noted in each origin. Statistically significant differences in ROH segment sizes were noted between the Jewish and the Israeli Arab/Druze origins in TRPS from 1% to 9.99%, whereas extremities of low (0.11%–0.99%) and high (over 10%) TRPS yielded no significant differences. In conclusion, as fixed absolute size thresholds may overlook pathogenic segments in certain populations while generating excessive reports in others, tailored approaches to define ROH reporting thresholds can be considered to facilitate the accuracy and clinical relevance of genomic analyses.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987189","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}

{"title":"Heterozygous loss of function variants in IFT140 are associated with polycystic kidney disease","authors":"Dinah Clark,&nbsp;Robert Burns,&nbsp;Michelle S. Bloom,&nbsp;Karen Phaik Har Lim,&nbsp;Lili Li,&nbsp;Lisa M. Vincent,&nbsp;Jing Xie,&nbsp;Yuan Xue,&nbsp;Sumit Punj","doi":"10.1002/ajmg.a.63841","DOIUrl":"10.1002/ajmg.a.63841","url":null,"abstract":"<p>Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in 1000 adults. Most cases result from causative <i>PKD1</i> or <i>PKD2</i> variants. <i>HNF1B, GANAB</i> and <i>ALG9</i> variants are also associated with ADPKD. Recent evidence indicates that monoallelic loss-of-function (LoF) <i>IFT140</i> variants are a cause for non-syndromic ADPKD. We describe 368 patients with <i>IFT140</i> LoF variants and a spectrum of phenotypic findings that support the association of <i>IFT140</i> with PKD. We reviewed patients with an unknown cause for their cystic disease and those with heterozygous LoF <i>IFT140</i> variants classified as pathogenic or likely pathogenic from a cohort that received genetic testing using a panel of 385 renal disease-associated genes. <i>IFT140</i> LoF variants were significantly enriched in patients with cystic disease when compared with those without cystic disease. A cystic phenotype was reported in 223 of the 368 (60.6%) individuals harboring an <i>IFT140</i> LoF variant, 98% of which had no other identified cause for their cystic disease. Of 122 unique LoF <i>IFT140</i> variants identified, 56 (46%) were frameshift, 38 (31%) nonsense, 22 (18%) splice site and 6 (5%) exon-level deletions. Only six <i>IFT140</i> individuals were reported with end-stage kidney disease, consistent with observed milder clinical presentations in <i>IFT140-</i>related PKD. This study offers further evidence for the involvement of LoF <i>IFT140</i> variants in PKD, particularly when no additional molecular etiology has been identified.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.63841","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}