American Journal of Medical Genetics Part A最新文献

Complex chromosomal rearrangements (CCRs) are structural variants involving multiple breakpoints. Among these, intrachromosomal balanced CCRs containing inversions pose significant diagnostic and interpretative challenges, as conventional cytogenetic methods including G-banded karyotype, FISH, and chromosomal microarray lack the resolution needed to determine their structural complexity. Paracentric inversions are traditionally associated with a negligible risk of a viable unbalanced offspring. Here, we describe a familial intrachromosomal rearrangement comprising a complex paracentric inversion of chromosome 6q, transmitted across multiple generations, that resulted in five affected children with recombinant chromosomes harboring reciprocal interstitial gains and losses on 6q. High-resolution optical genome mapping revealed a ~75 Mb parental balanced CCR, formed by multiple sequential paracentric inversions that contain a single ~13 Mb correctly oriented segment. Bias meiotic recombination between homologous chromosomes 6 within this segment is responsible for recurrent unbalanced products resembling recombinant chromosomes typically associated with pericentric inversions. These findings challenge the prevailing assumption that paracentric inversions rarely result in viable recombinant chromosomes and demonstrate how complex chromosomal architecture can directly influence meiotic behavior and reproductive outcomes. Our study underscores the importance of high-resolution genomic technologies for accurate diagnosis, interpretation of a molecular mechanism, and reproductive risk assessment in carriers of CCR.

Pulmonary arteriovenous malformations (PAVMs) are rare vascular anomalies most commonly seen in hereditary hemorrhagic telangiectasia (HHT), a condition associated with mutations in ENG, ACVRL1, SMAD4, or GDF2. In contrast, BMPR2 variants are well-established in heritable pulmonary arterial hypertension (PAH), but their relationship to PAVMs remains poorly understood. We report the case of a 41-year-old woman with an incidentally discovered PAVM, initially treated with embolization and subsequent surgical resection. She remained asymptomatic for several years until progressive exertional dyspnea led to a diagnosis of severe precapillary PAH. Genetic testing identified a heterozygous BMPR2 splice-site variant (c.967 + 5G>A), previously reported in a PAH cohort but currently classified as a variant of uncertain significance. This report is notable for the delayed evolution from isolated PAVM to PAH in the context of a BMPR2 variant, raising the possibility of a mechanistic link outside the canonical HHT pathway. We review published reports of BMPR2-associated PAVMs, some of which include subtle HHT-like features, such as mucocutaneous telangiectases and epistaxis, despite negative testing for classical HHT genes. These observations suggest a potential phenocopy vascular syndrome driven by disruption of the shared bone morphogenetic protein 9 (BMP9)-ALK1 signaling axis. We also discuss the implications of sotatercept, a transforming growth factor-beta (TGF-β) superfamily ligand trap, which in this case was associated with symptomatic improvement and stable shunt burden. These findings contribute to the emerging recognition of atypical vascular phenotypes in BMPR2 variant carriers, particularly those presenting with PAVMs in the absence of HHT. It highlights the importance of considering genetic testing in isolated AVM presentations, as well as the need for longitudinal surveillance and mechanistic investigation into overlapping TGF-β/BMP signaling disorders.

Evaluate the application efficacy of trio exome sequencing (Trio-ES) in prenatal families with a history of developmental delay/intellectual disability (DD/ID). This cohort study enrolled prenatal families with a family history of DD/ID from a single center between January 2020 and May 2025. We included 104 prenatal families that had excluded copy number variation abnormalities but had not undergone single nucleotide variant testing. Based on family history, these families were divided into two groups: those with a history of DD/ID births but phenotypically normal parents (lacking proband samples), and those without a history of DD/ID births but with one or both parents having ID. The overall positive rate of prenatal Trio-ES among 104 families with a history of DD/ID was 21.15% (22/104). Among 81 families with a history of DD/ID births but phenotypically normal parents, the positive rate was 13.58% (11/81), including 7.41% (6/81) affected fetuses and 6.17% (5/81) only parents as carriers, both primarily exhibiting a recessive inheritance pattern. Additionally, the positive rate in non-syndromic DD/ID families was 11.54% (6/52), while it reached 17.24% (5/29) in syndromic DD/ID families (associated with epilepsy, dystonia, hearing impairment, abnormal head circumference, etc.). Among 23 families without a history of DD/ID births but with one or both parents having ID, the positive rate significantly increased to 47.83% (11/23), primarily driven by dominant variants. This study represents the first focused evaluation of the clinical utility of Trio-ES in prenatal families with a history of DD/ID when proband samples are unavailable. We recommend actively employing Trio-ES for prenatal genetic evaluation in such families, particularly those presenting with a syndromic phenotype.

VariantMatcher is a web-based platform developed to share variant-level genomic data and phenotypic information. Here, we describe the experience of a clinical laboratory in Brazil, DASA, utilizing VariantMatcher to enhance variant classification in a clinical setting. We retrospectively analyzed 3025 molecular genetic test results to identify variants classified as variants of uncertain significance (VUS). Of 2302 reported variants, 1679 were classified as VUS. Next, we selected the 542 VUS not described in gnomAD to investigate their presence in VariantMatcher. Of these 542, 80 variants were present in VariantMatcher. Sixty-three of them were identified in individuals with a phenotypic overlap. Further investigation of the phenotypic features of individuals with the same variants led to the reclassification of 20 (32%) of the 63 variants. Notably, most of the reclassifications helped rule out the queried variant as causative for the phenotype being investigated, particularly for autosomal or X-linked dominant diseases with early onset and complete penetrance. Our experience supports the benefits of data sharing in the clinical setting, which can improve variant classification accuracy and provide more precise guidance for informed clinical decision-making.

Molecular characterization of balanced complex chromosomal rearrangements (CCR) aids in understanding the pathophysiological mechanism and corresponding genotype-phenotype correlations. The present case describes a male child with intellectual disability, developmental delay, and dysmorphism. A thorough and sequential genetic evaluation using karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray (CMA), and long read sequencing (LRS) identified a genomically balanced CCR. The CCR involved eight chromosomes, the largest to be documented till date for chromoanagenesis and being balanced despite the high level of complex chromosomal involvement. Translocations accounted for the majority of the rearrangements along with an insertion, inversion, and a small deletion likely driven by chromoplexy. Although the CCR was genomically balanced, it may still result in functionally significant genomic consequences including gene disruptions, gene fusions, and position effects. Long read whole genome sequencing using PacBio was used for breakpoint characterization that revealed three protein-coding genes to be disrupted, namely, NLGN4X, LAMA4, and ALG6. Of these, a candidate association was observed for the NLGN4X gene with the intellectual disability phenotype reported in the proband, which is likely due to disruption of transcription and nonsense mediated decay. We show combinatorial application of advanced genomic technologies with orthogonal cytogenetic techniques in delineating balanced CCRs and understanding the biological and potential clinical implications of balanced yet functionally disruptive CCRs.

Variants in the keratin 6A (KRT6A) gene are a major cause of pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by nail hypertrophy and other ectodermal abnormalities. This study aimed to identify the causative mutation in a PC family and investigate the underlying pathogenic mechanism. We performed exome sequencing on this PC pedigree and validated candidate variations using Sanger sequencing. In silico predictions and in vitro experiments showed that the heterozygous missense variant c.512A>G in KRT6A was pathogenic, inducing protein aggregation and disrupting filamentous network structures. Enrichment analysis suggested that the PPAR signaling pathway played a crucial role in PC, with decreased expression of PPARβ/δ in HeLa cells. Comparative analysis of PC patients carrying the p.Asn171 variant revealed marked heterogeneity in clinical manifestations. Notably, oral leukokeratosis, a common phenotype in KRT6A mutation carriers, was not observed in the patients in this study. Interestingly, one patient presented with small papules around the lips and nasal bridge. We conclude that the c.512A>G variant in KRT6A is the genetic cause of this PC family, diagnosed as PC-K6a subtype. This study expands the phenotypic spectrum of congenital PC and suggests the PPAR signaling pathway as a potential therapeutic target.

Pathogenic variants in PIGG (phosphatidylinositol glycan anchor biosynthesis, class G) disrupt glycosylphosphatidylinositol (GPI) anchoring of cell-surface proteins. Recently, biallelic PIGG variants have been linked to motor neuropathy with conduction block and temporal dispersion, suggesting a role for defective GPI anchoring in peripheral nerve function. We describe a 27-year-old woman carrying a homozygous nonsense variant in PIGG, c.1515G>A (p.Trp505*), presenting with continuous lower limb myokymia, gait ataxia, tremor and distal weakness since early adolescence. Electrophysiological evaluation revealed widespread myokymic discharges on electromyography, consistent with peripheral nerve hyperexcitability, and a pure motor polyneuropathy with temporal dispersion. This case report expands the clinical spectrum of PIGG-related disorders by identifying peripheral nerve hyperexcitability as a defining feature. The potential mechanistic link between defective GPI anchoring and neuronal hyperexcitability mediated through impaired function of GPI-anchored proteins such as contactin-1 and contactin-2 offers a compelling hypothesis connecting peripheral neuropathy, hyperexcitability, and cerebellar dysfunction.

Pathogenic, biallelic variants in LIG3 are known to cause Mitochondrial DNA Depletion syndrome 20 with variable expression and severity. We describe a child with progressive encephalopathy, cataracts, movement disorder, endocrine dysfunction, and immunodeficiency who remained undiagnosed despite multiple negative clinical genomic diagnostic studies. Research reanalysis of PacBio long-read genome sequencing data identified compound heterozygous LIG3 variants, including a splice variant and a novel 98 bp insertion. Western blot confirmed loss of LIG3 protein expression and RNA-seq demonstrated aberrant transcripts. Muscle biopsy revealed mitochondrial dysfunction, with COX-deficient fibers and complex IV deficiency. Notably, this is the first reported association of LIG3 deficiency with immunologic and endocrine abnormalities, emphasizing the importance of a broad approach to phenotype-genotype.

To date, only two families with variants in the IQSEC1 gene associated with intellectual developmental disorder with short stature and behavioral abnormalities (IDDSSBA) have been described. Here, we report an 8-year-old boy with short stature, speech delay, dysmorphic facial features, hypotonia, and behavioral disorders, as well as corpus callosum dysgenesis associated with compound heterozygous variants Pro1095ArgfsTer97 and Thr485Met in the IQSEC1 gene. To our knowledge this is the first report of brain anomalies associated with IQSEC1 variants, highlighting the need for MRI in affected patients.

Xia-Gibbs Syndrome (XGS; MIM: 615829) is a rare neurodevelopment disorder (NDD) caused by de novo pathogenic variants in the single coding exon of the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene. In this study, we investigate a rare case of double mosaicism in a 10-year-old female with XGS. The proband presented with characteristic clinical findings observed in XGS, including severe developmental delay, hypotonia, seizures, and dysmorphic features. Initial clinical genetic testing reported two adjacent de novo arising variants in AHDC1 (c.1167delG and c.1169delC), each present with an approximately 30%-36% allelic fraction in genomic DNA from a blood sample. In order to establish the haplotype phase of the variants, we performed long-read whole genome sequencing of DNA from an additional blood sample and short-read amplicon sequencing with blood and buccal swab samples. These data indicated that the adjacent variants are in trans on the same parental haplotype, likely originating in the zygote. These findings indicate a rare occurrence of double mosaicism and provide insights into the mechanisms behind somatic mutations influencing early development. The case underscores the importance of advanced molecular techniques in resolving complex genetic events and their impact on clinical presentations in XGS.