American Journal of Medical Genetics Part A最新文献

Homozygous achondroplasia is widely considered perinatal lethal by the medical community. In this case series, we report two children from a single family with longer-term survival. One child lived for 17 months and the other was 60 months at the time of publication. We describe two siblings born to parents with achondroplasia with homozygous achondroplasia and long-term survival.

Trichothiodystrophies (TTDs) are a group of disorders that have been characterized by sparse, brittle, and sulfur deficient hair that showed a "tiger-tail" banding pattern. Though the majority of TTDs are inherited in an autosomal recessive pattern, RNF113A related trichothiodystrophy is X-linked. RNF113A-related TTD has been associated with a non-photosensitive trichothiodystrophy, characterized by intellectual disability, microcephaly, growth restriction and failure, genital abnormalities, endocrine abnormalities, recurrent infections, and abnormal brain magnetic resonance imaging (MRI). To date, six individuals have been described with RNF113A-related TTD. Here we describe two brothers in their 30's with a novel hemizygous variant c.635G>A p.Gly212Asp in the RNF113A gene, which is not present in the tissues tested in their mother. Protein modeling suggests significant structural alteration. The brothers are the oldest known affected individuals and have features consistent with X-linked trichothiodystrophy including intellectual disability, microcephaly, growth failure, dysmorphic features, severe myopia and tiger-tail banding pattern. Absence of endocrinological abnormalities, recurrent infections, genital abnormalities, and abnormal MRI showed that these are not universal findings of RNF113A related trichothiodystrophy. Given that absence of the variant in the patients' mother, we presume the mother to have low level somatic mosaicism or germline mosaicism for the variant. This highlights the importance of genetic counseling for accurate recurrence risks and warranted reproductive testing for parents and female siblings of affected individuals with presumed de novo variants.

Pathogenic variants in NCKAP1, a gene encoding a core component of the WAVE regulatory complex (WRC), have recently been implicated in neurodevelopmental disorders (NDDs), but the clinical spectrum remains incompletely characterized. We describe a father and daughter carrying a novel heterozygous NCKAP1 splice-site variant (c.2021+1G>A), both presenting with developmental delay, autistic features, epilepsy, and shared craniofacial dysmorphisms. Although familial cases have been previously reported, this is the first to present thorough phenotypic documentation, including longitudinal neurodevelopmental and neuroimaging follow-up, dermatologic involvement, and dysmorphic evaluation in both the parent and the child. Notably, both individuals showed nail dystrophy and inflammatory skin lesions, expanding the phenotypic range of NCKAP1-related disorders beyond the nervous system. Comparative analysis revealed significant overlap with reported features of RAC1, CYFIP2, and WASF1-related syndromes, genes that also encode components of the WRC, further supporting a shared pathophysiological mechanism involving cytoskeletal dysregulation. Expression data from GTEx and HPA confirm that NCKAP1 is not only neuronally expressed but also found in epithelial tissues, providing biological plausibility for the dermatologic manifestations. This report contributes new clinical insights into NCKAP1-associated NDDs and emphasizes the importance of detailed phenotyping in rare familial cases to refine gene-disease associations.

The prognosis in Binder phenotype is influenced by underlying etiology and associated findings. Genetic testing till date has focused on chromosomal anomalies and targeted testing of genes like ARSL (previously ARSE). The aim of this study was to assess the utility of exome sequencing in fetuses with antenatal Binder phenotype and explore how its results influence parental reproductive decision-making. This retrospective study included 50 fetuses with sonographic features of Binder phenotype who underwent exome sequencing with copy number variant calling. Semi-structured follow-up interviews were conducted with families to understand the rationale behind reproductive decisions. Pathogenic or likely pathogenic variants were detected in four cases, while phenotypically relevant variants of uncertain significance were observed in six additional cases. Notably, variants in GNPTAB, a novel association, were identified in two unrelated cases. Of the 31 families who awaited test results, 20 continued the pregnancy, while 7 chose termination despite negative or uncertain findings. Overall, 55% of pregnancies were electively terminated, driven by variant findings, ultrasound severity, recurrence, or previous outcomes. Genetic testing provided meaningful insights in select cases, but reproductive decisions were influenced by a broader range of clinical and psychosocial factors. We conclude that exome sequencing can support but does not dictate prenatal decision-making.

DEAF1-associated neurodevelopmental disorder (DAND) is a neurodevelopmental spectrum disorder caused by two methods of inheritance: the autosomal dominant intellectual disability syndrome (Vulto-van Silfout-de Vries syndrome (VSVS), OMIM #615828), and the autosomal recessive Neurodevelopmental disorder with hypotonia and impaired expressive language with or without seizures (NEDHELS OMIM #615828) (OMIM 617171). All reported cases of VSVS have occurred de novo. In this report, we describe the case of a 2-year-old male with a history of autism spectrum disorder and behavioral concerns who was identified to be heterozygous for the c.837C>G (p.C279W) pathogenic variant in DEAF1. Functional assays demonstrate that the p.C279W variant alters DEAF1's transcriptional repression activity. This variant was also identified in his 26-year-old mother, who also has a history of autism and speech delay. To the best of our knowledge, this is the first reported case of the dominant form of DEAF1-associated neurodevelopmental disorder inherited from an affected parent.

We report two siblings harboring a homozygous MGME1 variant, NM_052865.4:c.818 T>A; p.(Val273Glu), both presenting with ptosis, myopathy, scoliosis, and gastrointestinal symptoms. The index patient developed progressive, medically refractory dilated cardiomyopathy and underwent successful orthotopic heart transplantation (OHT). Reanalysis of previously negative WES identified the variant in the index case, and segregation by Sanger sequencing confirmed homozygosity in both siblings. Although several clinical findings overlap with previously described MGME1-related disease, the detected variant remains classified as a variant of uncertain significance (VUS); thus, functional evidence is needed to better understand its potential causal relevance. Additionally, this report underscores the importance of periodic genomic data reanalysis and highlights the variable expressivity that may occur even within the same family.

RASopathies are clinically overlapping neurodevelopmental syndromes resulting from germline mutations in genes involved in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway. Historically, RASopathies have been described by clinical phenotypes, such as Noonan syndrome and Neurofibromatosis type I. There is emerging evidence of the association between Noonan syndrome spectrum disorders (NSSD) and systemic lupus erythematosus (SLE). Here, we present an SLE patient diagnosed with SOS1-associated Noonan Syndrome (c.806 T>C; p.Met269Thr) as part of a research study. Reviewing the literature, we identified further 16 cases of NSSD associated with SLE. Nine out of 16 cases (56%) had a confirmed molecular diagnosis, with pathogenic missense variants identified in KRAS, PTPN11, and SHOC2 genes, the majority in the last. Variants in SHOC2 are the cause of only a small proportion of all presentations of NSSD. Our case represents the first reported case of SLE in a patient with a SOS1 pathogenic variant. Compared to the general SLE population, SLE in the presence of NSSD develops at a younger age, with a similar prevalence among females and males, suggesting a contribution of the RAS/MAPK pathway in the development of SLE.