American Journal of Medical Genetics Part A最新文献

People with Phelan-McDermid syndrome (PMS) have reduced speech and language abilities, yet little research has profiled the communication abilities in this population. The purpose of this study was threefold: identifying the language and communication profiles of school-aged children with PMS, identifying genetic contributions to language and communication abilities, and determining the feasibility of remote data collection for research purposes. A speech language pathologist used standardized assessments and direct evaluations by video conferencing to evaluate language and communication abilities. Sixteen children and adolescents were evaluated: 5 with SHANK3 pathogenic variants, 9 with 22q13 deletions including SHANK3 (PMS-SHANK3 related), and 2 with 22q13 deletions preserving SHANK3 (PMS-SHANK3 unrelated). All showed moderate-to-severe language impairment across all assessments. Females demonstrated higher communication abilities than males. Haploinsufficiency of SHANK3 appears to be the main driver of language impairment in PMS; however, participants with preserved SHANK3 also scored in the impairment range, suggesting other contributions from 22q13 genes to the language phenotype. This study demonstrates the efficacy of using standardized instruments and remote data collection methods to assess communication in PMS. Remote methods may be helpful for the assessment of other genetic disorders involving language phenotypes.

The RASopathies are a group of congenital disorders with overlapping clinical manifestations that are caused by pathogenic germline or early somatic variants that result in the hyperactivation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. Given the heterogeneous clinical presentations of these disorders that involve abnormalities across multiple organ systems, multidisciplinary clinical management and progress in scientific research are essential for optimal patient diagnosis and care. The 9th International RASopathies Symposium, a biennial meeting, was organized by the patient advocacy group RASopathies Network and showcased recent discoveries, case studies, and advances in preclinical research. Participants, who included scientists, clinicians, industry representatives, patients, and family advocates, explored knowledge gaps, innovative clinical approaches, and lived experiences of individuals with a RASopathy. Sessions centered around organ systems were introduced with a patient perspective to highlight the burden of disease, continued with presentations from established and early-career investigators. Overall, the RASopathies Symposia serve as a catalyst for sustained community collaboration focused on enhancing patient health and accelerating the translation of discoveries into effective treatments.

Only a few studies describe five (or more) patients with inherited glycerol-3-phosphate dehydrogenase 1 (GPD1) deficiency, often termed transient infantile hypertriglyceridemia (HTGTI). We report 18 additional patients with HTGTI (confirmed molecular diagnosis in 16, a variant of uncertain significance in two), most of whom presented in infancy with hepatomegaly. A significant negative correlation was noted between age at presentation and serum triglyceride levels. Except for two, all our patients have homozygous GPD1 variants, wherein the c.500G>A (p.Gly167Asp) variant was the most common (10 patients). Other variants identified included c.220-1G>T, c.398C>T (p.Ser133Leu, unpublished), c.806G>A (p.Arg269Gln), and c.685C>T (p.Arg229Trp, novel). Homozygosity matching in patients with the biallelic c.500G>A variant showed that the GPD1 gene is located within the only shared region of homozygosity (> 1 Mb). These patients also have a similar homozygous haplotype around the variant, construing its founder effect in South Asian patients with inherited GPD1 deficiency. Targeted testing for c.500G>A could be considered as a first-tier evaluation strategy in South Asian patients with HTGTI. However, given our limited sample size, further validatory studies are needed.

The rare X-linked female-restricted Hardikar syndrome (HDKR, OMIM # 301068) is characterized by multiple congenital anomalies including orofacial clefts, gastrointestinal, genitourinary, and cardiac anomalies, but cognitive and neurobehavioral development is rarely impaired. HDKR is caused by heterozygous frameshift, splice or nonsense variants in the MED12 gene. Besides HDKR, MED12 pathogenic variants cause a broad spectrum of developmental disorders, collectively referred to as MED12-related disorders, including Opitz-Kaveggia syndrome or FG syndrome type 1 (OKS, OMIM #305450), Lujan-Fryns syndrome (MRXSLF, OMIM #309520), X-linked Ohdo syndrome (OHDOX, OMIM #300895) and isolated intellectual disability. Here we report four individuals with HDKR, including the first of maternally inherited HDKR, and we review molecular and clinical data from 33 individuals with HDKR and 215 individuals with other MED12-related disorders retrieved through a literature and public database search. We highlight sella turcica cysts as a new Hardikar syndrome-related feature, and we introduce clinical guidelines for the diagnosis and management of individuals with HDKR.

Carpenter syndrome type 2 (CRPT2) is a rare autosomal recessive disease mainly characterized by craniosynostosis and polysyndactyly. CRPT2 is the rarer subtype of Carpenter syndrome (CRPTS) and is caused by biallelic variants in the multiple epidermal growth factor-like domains 8 gene (MEGF8). Due to its rarity and phenotypic overlap with other craniosynostosis syndromes, definitive molecular diagnosis of CRPT2 can be challenging. Here, we describe a proband with CRPT2 carrying compound heterozygous variants in MEGF8: one de novo variant disrupting splicing and a maternally inherited missense variant. To resolve these variants, we leveraged long-read genome sequencing to phase the missense variant alleles and RNA sequencing to determine splicing impact. This case highlights the diagnostic value of using sequencing methods beyond the more conventional short-read exome sequencing. Our findings expand the spectrum of MEGF8 variants causing CRPT2 and underscore the utility of emerging sequencing technologies in elucidating complex or previously unresolved genotypes. Expanding access to such technologies is anticipated to accelerate rare disease diagnosis and deepen our understanding of the genetic mechanisms underlying these conditions.

The embryonic development of the cerebellum is orchestrated through a dynamic process that governs the interplay of Purkinje and granule cell populations. SKOR2 (Fussel 18) is a transcriptional co-repressor that increases SHH (sonic hedgehog) expression which is a potent signal for granule cell proliferation and integration into the complex neuronal network that underlies cerebellar function and development. Complete loss of Skor2 function in a murine model has been shown to result in cerebellar hypoplasia due to severe disruption of the cerebellar vermis. Through GeneMatcher we identified eight individuals from five unrelated families with compound heterozygous or homozygous loss of function, splice site and missense variants in SKOR2 associated with a phenotypic spectrum of cerebellar hypoplasia, microcephaly, ataxia, developmental delays and intellectual disability. Variants identified in SKOR2 included homozygous c.1877delC; p.Pro626Glnfsx156 in the first individual, homozygous c.2752 + 1G>T in the second and third individuals, compound heterozygous c.757T>G p.C253G, c.949T>A p.S317T in the fourth individual, homozygous c.421_424del (p.Asp141Ilefs*118) in the fifth, sixth, and seventh individuals, and a homozygous c.1169C>A; p.Ser390* in the eighth individual. The eight individuals had various degrees of developmental and speech delays, as well as cerebellar hypoplasia identified in some of them. In silico analysis supported pathogenicity of most of SKOR2 variants, except for case 4, and their impact on protein function. Recently, SKOR2 is reported to be associated with Valence-Farazi Cerebellar Ataxia Syndrome (OMIM # 621386) (Skor2-OMIM-OMIM.ORG). This study expands the phenotypic spectrum for this newly described condition. Additional studies in affected individuals will be needed to refine the phenotypic spectrum and identify genotype-phenotype correlations.

RASopathies are a group of genetic disorders caused by pathogenic variants in the RAS-mitogen-activated protein kinase (RAS-MAPK) signaling pathway, often presenting with congenital heart defects, craniofacial dysmorphisms, and developmental delays. To assess the diagnostic yield of genetic testing in patients with suspected RASopathies and to identify predictive clinical "red flags" using machine learning (ML). This retrospective study included patients evaluated at our institution between 2020 and 2023. All patients underwent cardiovascular evaluation, and a subset of individuals with suspected RASopathies underwent genetic assessment including exome sequencing. Thirteen clinical "red flags" were analyzed as predictors of a molecular diagnosis within the subgroup of patients with suspected RASopathies. Diagnostic performance was assessed via sensitivity, specificity, and area under the curve (AUC). A random forest classifier identified the most predictive clinical features. Among 669 patients, 34 were clinically suspected of RASopathy, with a confirmed diagnosis in 24 cases (71%). Noonan syndrome was most frequent (18/24), and PTPN11 was the most commonly mutated gene (n = 13). Pulmonary valve stenosis (PVS) and facial dysmorphisms were the strongest individual predictors of a positive genetic test result. A threshold of ≥ 2 red flags balanced sensitivity (92%) and accuracy (73.5%). ML analysis identified PVS and facial dysmorphisms as the top predictors. A model including only these features achieved an AUC of 0.86 in the derivation cohort. PVS and facial dysmorphisms are key diagnostic indicators for RASopathies and should prompt early genetic testing. While the ML model showed high performance in this derivation cohort, external validation is needed to confirm its generalizability.

GCNT2-related cataracts is a disorder characterized by bilateral congenital cataracts (CC) of various types (with or without the adult i blood phenotype) and is caused by biallelic variants in GCNT2, which has 3 major isoforms, differentiated by alternative splicing of the first exon (known as exon 1A, B, and C). While the transcript that includes exon 1C is thought to be key for the adult i blood phenotype, it is not clear which transcript(s) are clinically relevant for the CC disease phenotype. We report a proband with CC and a truncating variant in exon 1B (NM_001491.3: c.760dup p.H254Pfs*2) found in trans with a 75 kilobase (kb) copy-number deletion encompassing exon 1B and 1C. To our knowledge, c.760dup is the first reported disease-associated variant limited to exon 1B of GCNT2. This report strongly suggests that NM_001491.3, which includes exon 1B, is a clinically relevant transcript for GCNT2-related cataracts and adds to the variant spectrum for this understudied gene-disease relationship. This finding has implications for genotype-phenotype correlations of GCNT2 related CC and variant classification, particularly for truncations in exon 1B, which should likely receive strong pro-pathogenic weight based on this being a clinically relevant exon.

The key diagnostic criterion for hypertrophic cardiomyopathy is the presence of otherwise unexplained hypertrophy. Current definitions of HCM rely on specific thresholds to establish a diagnosis, while guideline directed risk stratification algorithms take its magnitude into consideration. Presently, secondary features such as myocardial crypts and valve abnormalities in the absence of hypertrophy are solely considered as markers of preclinical disease in variant carriers, with no perceptible excess risk for arrhythmic events. Strictly adhering to hypertrophy as the sole criterion for a diagnosis may at times result in delays in diagnosis of the condition in the proband and consequently initiation of family screening. At the same time, arrhythmic risk in individuals with minimal or no hypertrophy may be underestimated. In this study, we describe a novel ACTC1 variant expressed with arrhythmic instability in the proband, closely segregating in family members. The presenting phenotype is characterized by frank secondary abnormalities related to HCM in the absence of conventional wall thickness criteria to establish a formal diagnosis. Thereby, the description of this phenotype may challenge the established perception that hypertrophy is a prerequisite for establishing an HCM diagnosis.

We describe a male child with a de novo IRF2BPL c.2152del (p.Cys718Alafs*49) frameshift variant presenting with early-onset NEDAMSS and West Syndrome, and compare this phenotype with two previously reported cases carrying the same variant. This is the third report of this specific variant and the first to include a comparative phenotypic analysis, highlighting a potentially consistent and severe clinical pattern. The patient was identified through clinical evaluation and exome sequencing (ES) after presenting with early developmental regression and drug-resistant epilepsy. A literature search identified two additional cases with the same variant and a comparative analysis was conducted. The patient showed neonatal axial hypotonia, early neurodevelopmental regression and epilepsy evolving into West syndrome. Brain MRI revealed corpus callosum thinning and hippocampal malrotation. EEG evolved from burst-attenuation to hypsarrhythmia. ES identified a de novo c.2152del IRF2BPL variant. In comparison, all three cases shared profound hypotonia, severe neurodevelopmental impairment, and early-onset epileptic encephalopathy. These findings support the pathogenicity of the c.2152del variant and suggest its potential association with a severe early-onset NEDAMSS phenotype. Generalizability remains limited by the small number of cases, and confirmation requires further clinical and functional evidence.