American Journal of Medical Genetics Part A最新文献

The purpose of this study is to explore the phenotypic spectrum observed in individuals and between families with confirmed variants in the T-Box Transcription Factor 22 gene (TBX22). Pathogenic variants in TBX22 have been identified in individuals with classic X-linked cleft palate (CPX) and also in Abruzzo-Erickson Syndrome (ABERS). We compare the phenotypic features of a newly suspected family with ABERS to those of the original family with ABERS to help determine if family-specific pathogenic variants in TBX22 are the cause of ABERS. Furthermore, we discuss possible mechanisms of action of the identified TBX22 variants. We conducted an observational case series in a new family (Family B) suspected of having ABERS, and a retrospective review of participants in the original family with ABERS (Family A), as described by Abruzzo and Erickson (1977). Thirteen individuals from two different families were included in this case series. As previously reported in 2013, DNA samples from four individuals in Family A were screened for variants in TBX22, and each was found to carry the same unique pathogenic variant. Five individuals from Family B were screened for variants in TBX22, and the four with abnormal features were found to be positive for a new pathogenic variant; however, the variant segregating in this family differed from the one present in Family A. Despite this, there was considerable overlap between Family A and Family B in phenotypic features. Thus, we hypothesize that gain-of-function pathogenic variants in TBX22 are the probable cause of ABERS in both Family A and Family B.

DeSanto-Shinawi syndrome is a rare genetic disorder caused by pathogenic variants or deletions involving the WAC gene, located on chromosome 10p12.1, and is characterized by developmental delay, intellectual disability, and distinctive dysmorphic features. In addition to deletions encompassing WAC, several proximal deletions on chromosome 10 that exclude WAC have also been reported. Here, we describe a patient with a microdeletion of chromosome 10p11.23-p11.21 spanning approximately 4.2 Mb. The patient exhibited intellectual disability, agenesis of the corpus callosum, and congenital heart disease. The deleted region includes the following protein-coding genes: ZNF438, ZEB1, ARHGAP12, KIF5B, EPC1, CCDC7, ITGB1, NRP1, and PARD3, while WAC was preserved. Pathogenic variants or deletions of ZEB1 are known to cause corneal abnormalities and agenesis of the corpus callosum, whereas loss of NRP1 has been implicated in the pathogenesis of congenital heart disease. We therefore hypothesize that haploinsufficiency of multiple genes within the deleted region-particularly ZEB1, EPC1, KIF5B, and NRP1-may collectively contribute to the observed clinical phenotype. These findings suggest that microdeletions involving chromosome 10p11.2 are associated with a phenotype distinct from that of DeSanto-Shinawi syndrome.

TBC1 domain-containing kinase (TBCK; MIM #616900) is implicated in autosomal recessive neurodevelopmental disorders with hypotonia and developmental delay. TBCK regulates mTOR signaling, lysosomal activity, and intracellular trafficking, but the full spectrum of pathogenic variants remains poorly understood. We investigated a consanguineous Iranian family with psychomotor delay. Whole exome sequencing (WES) identified a candidate TBCK variant, confirmed by Sanger sequencing. Functional studies were performed using amniotic fluid-derived cell culture, Western blotting, protein structural modeling, and molecular docking analyses. A novel homozygous frameshift variant, TBCK (NM_001163435.3): c.1969dupT (p.Cys657Leufs*17), was detected and absent from population databases. Clinically, the proband presented with severe developmental delay, hypotonia, seizures, and facial dysmorphism, and died at 9 months. Western blotting showed a significant decrease in TBCK expression (p < 0.007). Structural analysis of a theoretically modeled truncated protein indicated C-terminal truncation with loss of critical domains, while in silico docking demonstrated reduced binding affinity between mutant TBCK and Rab1B, suggesting impaired Rab-mediated trafficking. This study reports a novel pathogenic TBCK variant associated with severe neurodevelopmental delay, contributing to the clinical and molecular spectrum of TBCK syndrome. Our findings underscore the importance of genetic testing in rare neurodevelopmental disorders and provide insight into the molecular mechanisms underlying TBCK dysfunction.

Biallelic variants in the STAMBP gene are known to cause Microcephaly-capillary malformation syndrome (MICCAP syndrome). Here we report an 18-month-old female with a novel splice site variant, c.376-1G>A in intron-4, with the phenotype of a patient who presented to us with fetal onset growth retardation, developmental delay, drug-resistant seizures, multiple capillary malformations, dysmorphism, tone abnormalities, and distal skeletal and nail abnormalities. Functional studies by RNA analysis and quantitative polymerase chain reaction (qPCR) showed that the variant leads to loss of function. The clinical features noted in this child strongly overlapped with the phenotypes reported in the literature, except for absent dentition and retinal dystrophy-like findings on fundus examination. A total of 22 cases have been reported in the literature. We present a detailed description of an Indian child, expanding the clinical and molecular spectrum of STAMBP-related disease.

Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a congenital disorder characterized by lymphedema, telangiectasia, and hypotrichosis or alopecia, caused by mutations in the SRY-related high-mobility group box (SOX) 18 gene. We report the case of a 10-year-old boy who presented with aortic valve regurgitation, marbled skin, minor anomalies, and iron-deficiency anemia due to frequent mucosal bleeding. At 5 years of age, he experienced significant hemostatic difficulties following the extraction of a deciduous tooth. The usual doses of iron supplementation did not cure his iron-deficiency anemia. Blood coagulation analysis revealed a decreased platelet agglutination capacity, associated with reduced von Willebrand factor (vWF) antigen levels and activity. Whole-genome sequencing at the age of 15 years did not identify any pathogenic variants in the VWF gene. However, this analysis revealed a heterozygous pathogenic variant of SOX18 (NM_018419.3: c.481C>T, p.Gln161Ter), which led to the diagnosis of HLTS. SOX18 plays a significant role in VWF expression in stem cells. vWF replacement therapy facilitated safe tooth extraction and stabilized hemoglobin levels. Decreased vWF may be a complication of HLTS, and vWF replacement therapy can significantly improve patients' quality of life.

Costello syndrome (CS) is a rare RASopathy that is typically associated with mild to moderate cognitive impairment. Based on detailed neuropsychological testing, this case series describes variability in the neurobehavioral presentations of three unrelated individuals with different pathogenic HRAS variants that cause CS. Results demonstrate a wide range of functioning among people with CS (extremely low to superior ranges) and describe the first cognitive testing results for an individual with HRAS c.179G>A, p.Gly60Asp. Patient-reported social, emotional, and quality of life outcomes also are discussed. These cases highlight the potential for above average cognitive functioning, the importance of flexible neurobehavioral assessment methods, and key quality of life and mental health domains to evaluate in individuals with CS.

Marden-Walker syndrome (MWS; OMIM 248700) is an extremely rare congenital disorder characterized by multiple joint contractures, craniofacial dysmorphism, neurological abnormalities, and multisystem involvement. Although historically diagnosed on clinical grounds, only a few cases have been molecularly confirmed. Here, we describe a Brazilian female infant with classic manifestations of MWS, carrying a heterozygous pathogenic variant in the PIEZO2 gene not previously reported in MWS. To our knowledge, this is the first molecularly confirmed MWS case from Brazil, thus expanding both the genotype-phenotype spectrum and geographic distribution of PIEZO2-related disorders. Comparative analysis of previously reported molecularly confirmed cases reveals shared core features and highlights the prominent neurological involvement observed in our patient. A review of individuals with the same PIEZO2 variant demonstrates marked phenotypic variability-from Gordon syndrome to distal arthrogryposis type 5-underscoring allelic heterogeneity and variable expressivity. This case refines the phenotypic spectrum of PIEZO2-related disorders and illustrates how allelic heterogeneity contributes to wide clinical variability, while also underscoring the importance of including underrepresented populations in variant interpretation.

Few studies describe the impact of rapid exome sequencing (ES) on pediatric cardiomyopathy in urgent clinical settings. Here, we retrospectively report the impact of rapid singleton ES in pediatric patients presented with acute heart failure and isolated cardiomyopathy or myocarditis, between 2021 and 2023 at a single tertiary care center. A total of nine patients were included; age range: 5 days-11 years (median 42 days). Eight patients (88.8%) presented in the first year of life. The turnaround time for the ES results was 5-14 days (median 9 days). The diagnostic yield was 5/9 (55.5%), confirming primary cardiomyopathy. The majority had dominant disorders (ACTC1, MYBCP3, TNNI3, and NKX2-5), with two (22.2%) occurring de novo. One patient had a recessive condition (MYBPC3). In three patients (33.3%) who rapidly deteriorated during hospitalization, ES results had a major impact on immediate medical management. In most patients, the diagnosis led to the avoidance of further metabolic workup, cardiac magnetic imaging and vitamin treatment. In two families with no prior history of cardiomyopathy, at-risk relatives were advised to initiate cardiac surveillance. Overall the results show high clinical impact due to a shorter time to diagnosis, a high diagnostic yield, an improved therapeutic approach, in addition to the facilitation of genetic counseling for family planning and cascade testing of relatives at risk.

Pathogenic variants in the SCN5A gene and its subunits have been identified in individuals with Brugada Syndrome. One such SCN5A variant, c.689T>C(p.Ile230Thr), was previously reported as disease-causing only in homozygous individuals, with heterozygous carriers being unaffected. Presently, we discuss the case of an adolescent patient who presented for further evaluation of pre-syncopal episodes with ECG findings consistent with Brugada pattern who on further genetic evaluation was found to be a heterozygous carrier of the pathogenic SCN5A c.689T>C(p.Ile230Thr) variant. This unique case allows us to think differently about heterozygous carriers for this specific mutation, and while the risk for developing a life-threatening arrhythmia may be low, heterozygous carriers may benefit from clinical monitoring to reduce the potential for adverse cardiac outcomes. A 17-year-old male presented after a pre-syncopal episode whose ECG demonstrated sinus bradycardia and type 1 Brugada pattern. Genetic testing revealed this patient to be a heterozygous carrier of a pathogenic SCN5A variant (c.689T>C(p.Ile230Thr)) which was also found in his father and brother, neither of whom had symptoms but did have ECG changes. He was diagnosed with Brugada Syndrome and advised to avoid known triggers. This case highlights the potential risk of severe cardiac arrhythmias in heterozygous carriers of the SCN5A c.689T>C (p.Ile230Thr) variant, previously thought to be benign. The 17-year-old patient, along with his asymptomatic father and brother who also carried the variant, exhibited ECG changes consistent with Brugada pattern. This finding suggests that heterozygous carriers may require closer monitoring and early intervention to prevent future life-threatening cardiac events.

Congenital myopathy-14 (CMYO14) is an ultrarare autosomal recessive disorder caused by biallelic variants in MYL1, with only four patients reported to date. We describe what is likely the fifth reported patient, a neonate with severe hypotonia, respiratory insufficiency, and skeletal anomalies showing distinct histological changes of skeletal muscle consistent with all previously described patients. The patient carried a novel homozygous intron variant (c.479-25T>C, p.(?)) in MYL1. RNA analysis of patient muscle demonstrated aberrant splicing, with inclusion of 19 bp from intron 4 in most transcripts, resulting in a frameshift and premature stop codon, and in-frame skipping of exons 4-5 in a minority of transcripts encompassing functional domains. In addition to core CMYO14 features, the patient presented with craniofacial anomalies not previously described. This case broadens the genotypic and phenotypic spectrum of MYL1-related disease and underscores the diagnostic importance of intron variants, highlighting the value of combining in silico splice prediction with functional RNA analyses.