American Journal of Medical Genetics Part A最新文献

Variations in Sex Characteristics (VSC), also referred to as intersex traits or Differences of Sex Development (DSD), encompass diverse chromosomal, gonadal, and anatomical sex traits. The full spectrum of VSC remains under-recognized, partly due to diagnostic approaches that prioritize classic VSC/DSD conditions. We developed a 103-term Focused Genitourinary VSC Glossary (FGV Glossary) using Human Phenotype Ontology (HPO) terms and screened 8359 Online Mendelian Inheritance in Man (OMIM) entries for inclusion. Associated genes were evaluated for coverage in clinical DSD panels and assessed in ClinVar for pathogenic variants linked to VSC/DSD phenotypes. We identified 539 OMIM entries (~6.4%) with at least one FGV Glossary term. These entries were enriched for genitourinary, breast, and endocrine phenotypes. Of 56 high-confidence VSC/DSD genes identified, 23 (41%) were absent from a current representative DSD gene panel. A curated ClinVar review showed that 3 of these 23 genes (DHX37, SPRY4, TBX3) had pathogenic variants clearly associated with VSC/DSD traits. Genome-wide sequencing should be prioritized in VSC/DSD diagnostics, consistent with current best practices, to improve diagnostic yield and guide comprehensive, multidisciplinary clinical care.

We report a biallelic likely pathogenic variant in the NRDC gene in two Iranian siblings with developmental delay, microcephaly, hypotonia, seizures, and absent speech. Exome sequencing (ES) identified a frameshift deletion in exon 15 of NRDC (NM_001101662.2): c.1702_1703del (p.Met568Valfs*2), confirmed to segregate with disease in the family. This is the second report implicating biallelic NRDC gene variants in neurodevelopmental disorders. Our findings expand the phenotypic spectrum and support a potential role for NRDC in severe neurodevelopmental delay.

Pathogenic variants in TAMM41 were recently linked to mitochondrial myopathy, presenting with neonatal hypotonia, generalized weakness, developmental delay, ptosis, and ophthalmoparesis. Here, we present a long-term follow-up of an additional case, a Brazilian patient harboring a novel TAMM41 variant in compound heterozygosity with a previously described pathogenic variant. Patient exhibited mild developmental delay, acquired independent gait, but subsequently developed motor regression and weakness associated with recurrent infections, severe axial involvement, and marked restrictive pulmonary dysfunction. Muscle biopsy revealed decreased COX and SDH staining, which may serve as an important diagnostic clue for this condition. This case expanded the genetic spectrum of TAMM41-related mitochondrial myopathy and provided a brief review of disorders associated with reduced SDH staining.

Cancer risk in children with VACTERL, a nonrandom co-occurrence of ≥ 3 defects (vertebral, anal, cardiac, tracheoesophogeal fistula, renal, and limb), remains unclear. We evaluated this association in a population-based study. We analyzed data from the Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study, a US registry linkage cohort. VACTERL was defined as the presence of ≥ 3 associated defects. Cox regression was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer risk before age 18 in children with VACTERL compared to children without birth defects. Kaplan-Meier analyses were used to estimate cumulative incidence of cancer in each group. Of 21,224,742 births, 2288 met VACTERL criteria; 8 developed cancer, 5 (63%) of whom were diagnosed with embryonal tumors. Children with VACTERL had a significantly increased cancer risk (HR = 3.0, 95% CI: 1.5-6.0), particularly for embryonal tumors (HR = 6.9, 95% CI: 2.9-16.5), relative to unaffected children. Cancer incidence was 421.3 (95% CI: 181.9, 830.0) per million person-years for VACTERL versus 133.4 (95% CI: 131.8-135.0) for unaffected children. Children with VACTERL may face increased cancer risk. Shared developmental or epigenetic mechanisms may underlie both conditions, highlighting efforts to identify subgroups that may benefit from targeted surveillance.

RTEL1 R1264H is a founder variant with a carrier frequency of 0.3%-1.0% in the Ashkenazi Jewish population. While biallelic RTEL1 R1264H causes a severe form of telomere biology disorder (TBD) presenting in childhood, the clinical significance of monoallelic carrier status has remained uncertain, limiting effective counseling and management. Here, we describe the clinical features, telomere lengths, and tumor somatic profiles of cancer patients found to be heterozygous for RTEL1 R1264H to evaluate for evidence of subclinical TBD in this population. Among 39,337 individuals who underwent RTEL1 germline analysis via MSK-IMPACT, 32 (0.08%) were incidentally found to be heterozygous for RTEL1 R1264H. Three individuals (9%) met diagnostic criteria for TBD based on compatible clinical features and telomere shortening, and two additional individuals (6%) had histories suspicious for TBD but did not have telomere length data available. Notably, 7 individuals (22%) experienced severe or fatal therapy-related toxicities, despite many lacking other clinical features of a TBD. These findings support that RTEL1 R1264H can act in an autosomal dominant fashion and confer TBD disease risk, albeit with low penetrance, and may increase susceptibility to treatment-related complications.

Plexin-A1 is involved in axonal guidance in the developing human brain. Variants in the PLXNA1 gene are associated with a neurodevelopmental disorder characterized by early-onset epilepsy, intellectual disability, syndromic features, and brain and eye anomalies. We report a 19-month-old boy who presented with global developmental delay, right-sided ptosis, and a growth pattern above the expected range. Malformations of cortical development in the form of focal pachygyria and polymicrogyria were also observed. Cytogenetic microarray and trio whole-exome sequencing done in 2020 failed to detect any candidate variants. On re-analysis of the exome in 2025, we detected a novel homozygous splice site variant in PLXNA1:c.4870+1G>A. This variant is predicted to cause aberrant splicing and premature truncation of the protein. The clinical features of pachygyria with polymicrogyria and growth pattern above the expected range are novel and contribute to the growing phenotypic spectrum of PLXNA1-related neurodevelopmental disorders.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

Congenital disorders of glycosylation (CDG) are a heterogeneous group of metabolic diseases caused by defects in glycan biosynthesis, predominantly affecting the N-glycosylation pathway. Pathogenic variants in the DDOST gene, encoding a non-catalytic subunit of the oligosaccharyltransferase (OST) complex, underlie an ultra-rare CDG subtype with only three patients reported to date, complicating diagnosis and genotype-phenotype correlations. We describe a female patient with developmental delay, hypotonia, and dysmorphic features. Genetic analyses included chromosomal microarray, FMR1 testing, and trio-based next-generation sequencing with a neurodevelopmental disorder panel. Variants were assessed using ACMG criteria, population databases, segregation, and in silico analysis. We also reviewed published DDOST-CDG cases to compare clinical and molecular findings. Compound heterozygous DDOST variants were identified: (i) a maternally inherited 413-kb deletion encompassing exons 3-11, predicted to abolish gene function, and (ii) a paternally inherited in-frame deletion (p.Lys435del), removing a highly conserved residue in the luminal C-terminal domain. Both were absent from population databases and classified as pathogenic or likely pathogenic, consistent with autosomal recessive inheritance. Metabolic testing confirmed a type I transferrin isoform pattern, supporting a congenital disorder of glycosylation. This report expands the genetic and phenotypic spectrum of DDOST-CDG by describing the first structural variant. Review of published cases highlights hypotonia and motor delay as consistent features, while other traits such as strabismus, feeding difficulties, or hepatic dysfunction appear variable. Our findings underscore the clinical heterogeneity of DDOST-CDG and the complementary role of metabolic and genomic testing.