Clinical Genetics最新文献

UBTF codes for a nucleolar transcription factor required for transcription of rDNA genes. UBTF gain-of-function (GoF) has been identified as the cause of CONDBA syndrome, with a recurrent missense change, p.Glu210Lys occurring in most affected individuals. More recently, eight subjects with truncating variants or microdeletions involving UBTF have been associated with a distinct neurodevelopmental disorder in which developmental delay (DD) and intellectual disability (ID) co-occur with behavioral anomalies in the absence of signs of neuroregression. Here, we report on four affected individuals, including one adult subject, from a single family carrying a heterozygous UBTF splice-site variant affecting transcript processing. All subjects presented with a clinical phenotype characterized by DD/ID with behavioral problems, without signs of neuroregression. By systematically examining the clinical features in both current and previously reported cases, we identify a characteristic facial gestalt as a hallmark of the disorder, and recognize increased BMI and a hyper-nasal voice as previously underappreciated features. These data provide further evidence that UBTF haploinsufficiency causes a non-regressive form of DD/ID clinically distinct from CONDBA syndrome.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits high prevalence in malaria-endemic regions and areas along the historic Maritime Silk Road. This study investigated the burden and genetic architecture of G6PD deficiency in Nanning, the ethnically diverse capital of Guangxi in southern China, where Southeast Asian gene flow has shaped population genetics. We screened 14 403 individuals for G6PD activity at The First Affiliated Hospital of Guangxi Medical University, defining deficiency as activity < 60% of adjusted male median (AMM = 2045 U/L). Among 2513 deficient cases (prevalence: 17.45%), frequency was significantly higher in males (63.75%) vs. females (36.25%; p < 0.001) and Han Chinese (60.92%) vs. Zhuang (39.08%; p = 0.925). Multiplex melting curve analysis (MMCA) of 2513 enzyme-deficient samples identified pathogenic mutations in 1161 cases, revealing 13 distinct variants. The predominant mutations were: c.1388G>A (39.53%; 459/1161), c.1376G>T (24.81%; 288/1161), and c.95A>G (12.40%; 144/1161). Mutation c.871G>A exhibited male bias (p < 0.001), while c.95A>G was Zhuang-enriched (p < 0.001). Sanger sequencing of MMCA-negative cases identified two rare pathogenic variants (c.406C>T, c.196T>A). Our findings establish Nanning as a region of exceptionally high G6PD deficiency prevalence and delineate a distinct mutation profile with sex- and ethnicity-linked distributions. These results provide critical insights for designing precision screening programs and public health strategies tailored to this genetically diverse population.

We describe three unrelated individuals with congenital generalized hypertrichosis with gingival hyperplasia (CGHGH), each carrying a distinct structural rearrangement (duplication, deletion, inversion) at 17q24.2-q24.3 identified by CMA and WGS. Despite differences in the type of rearrangement, all three patients seem to exhibit alterations affecting the genomic architecture of a cluster of genes, particularly involving the ABCA family (notably ABCA5, ABCA6, ABCA9, ABCA10), MAP2K6, and potassium channels (KCNJ16, KCNJ2). These findings suggest that disruption of the local chromatin organization, including topologically associating domains (TADs), may contribute to the pathogenesis of CGHGH. Although previous studies implicated deletions affecting ABCA5 as the likely cause of CGHGH, our findings emphasize a broader spectrum of structural variation capable of producing similar phenotypes. Interestingly, one patient involved a cryptic 1.2 Mb inversion that disrupted the region between ABCA9 and KCNJ2, detectable only by whole genome sequencing, reinforcing the need for advanced molecular diagnostics in patients with syndromic hypertrichosis. In all three individuals, gingival overgrowth co-occurred with typical facial features, coarse hair, and normal cognitive development, adding evidence to the phenotype-genotype correlation. Overall, this study strengthens the hypothesis that disruption of regulatory elements and chromatin architecture at 17q24.2-q24.3, rather than single nucleotide variants alone, can be a primary driver of CGHGH. These findings underscore the need to incorporate genome-wide structural variant analysis in the diagnostic workflow of rare developmental disorders, especially those with heterogeneous or subtle clinical presentations.

The SMARCA4 gene encodes a catalytic subunit of the BRG1/BRM-associated factor complex, which regulates gene expression through chromatin remodeling. Heterozygous missense variants in this gene have been linked to Coffin-Siris syndrome, characterized by intellectual development disorder and various congenital anomalies (distinctive facial features, hypoplastic fifth digits, and malformations of the heart and central nervous system), but it is not typically associated with structural eye anomalies. Truncating variants in SMARCA4 have been associated with rhabdoid tumors predisposition syndrome, a group of rare and aggressive tumors occurring predominantly in infancy. Through pangenomic analyses (whole-exome or whole-genome sequencing), we identified loss-of-function variants in SMARCA4 in three unrelated individuals with microphthalmia and/or coloboma. None of these individuals had a history of rhabdoid tumors; however, a regular oncological follow-up was established following the SMARCA4 variant identification. Systemic features observed in these individuals consisted of developmental delay and brain anomalies. However, their clinical presentation does not align with classic features of Coffin-Siris syndrome. Although eye development anomalies have occasionally been reported in individuals with a pathogenic variant in SMARCA4, no clear association has been established to date. The description of these three new individuals provides further evidence supporting the role of SMARCA4 in eye development and its likely involvement in structural eye malformations.

Distal arthrogryposis constitutes a highly heterogeneous group of disorders with a critical need for clear classification. Phenotypes have traditionally been characterized using the classification system proposed by Bamshad or Hall for distal arthrogryposis. Recessive MYH3 inheritance has been described in contractures, pterygia and spondylocarpotarsal fusion syndrome, and, more recently, in distal arthrogryposis without skeletal fusion. We hereby report a nuclear family affected by distal arthrogryposis with biallelic MYH3-related disorder, identifying two novel variants, which in the heterozygous state yield a subclinical phenotype. Beyond refining the molecular diagnosis and guiding genetic counseling, our study emphasizes that the classification of MYH3-related disorders and their inheritance modes is still evolving, underscoring the need to integrate knowledge gained from careful analyses.

Müllerian anomalies are a collection of heterogeneous anatomical disorders of the female genital tract that present with complex clinical features of which severe subtypes like congenital aplasia of the vagina and uterus, may present with primary amenorrhea and dyspareunia, while mild cases like septate uterus, are often asymptomatic. Regardless of the types, the Müllerian anomalies impose both psychological and physical burdens on patients. Currently, the etiology of Müllerian anomalies remains largely unclear, which hinders early diagnosis and intervention. Although the advent of next-generation sequencing technologies has promoted a more comprehensive depiction of genetic features of Müllerian anomalies, there is still a lack of experimental validation for the functions of these genes, where some novel preclinical models having been applied in cancer fields may provide potentially available strategies. Thus, in this review, we aim to summarize the genetic defects and novel validation techniques associated with Müllerian anomalies. Elucidating the genetic mechanisms involving Müllerian anomalies can pave the way for the development of early diagnostic strategies and preventional measures in the future.

STEAP3 (Six-transmembrane epithelial antigen of the prostate 3), a metalloreductase, plays a key role in various cell processes, including iron homeostasis, inflammation, and cancer promotion. Over a decade ago, researchers reported a single, heterozygous nonsense variant in STEAP3 linked to transfusion-dependent severe hypochromic anemia. However, a later large population study on STEAP3 found no phenotypic red cell changes in heterozygous individuals. While the genotype and phenotype of STEAP3 are tentatively established for hypochromic microcytic anemia with autosomal dominant inheritance (MIM: 615234), we describe an autosomal recessive form of STEAP3-related neonatal familial hemophagocytic lymphohistiocytosis (HLH). We expanded the phenotype to include cytopenia and neonatal HLH. Our report on two affected male siblings highlights the expanded phenotype, clarifies the phenotypic spectrum of STEAP3, and broadens its genetic inheritance, ultimately providing a clinical and molecular workup for neonatal patients with unexplained HLH.

A Japanese boy carried a paternally inherited single-nucleotide deletion in PTF1A exon 1 (c.775delC) and a maternally inherited nucleotide substitution in the distal enhancer region (g.23508356T>G). Both variants were hitherto unreported. The patient exhibited transient anemia in addition to typical clinical features of pancreatic hypoplasia, but no neurodevelopmental abnormalities. These results highlight the clinical importance and broad mutation spectrum of PTF1A variants as a cause of pancreatic hypoplasia. In addition, our data imply that phenotypes of PTF1A abnormalities are variable and include etiology-unknown transient anemia.

Copy number variations (CNVs) affecting the imprinted regions in 11p15.5 (imprinting centre 1 and 2/IC1, IC2) account for more than 2% of the molecular disturbances in Beckwith-Wiedemann and Silver-Russell syndrome (BWS, SRS) and are associated with a recurrence probability of up to 50%. However, their clinical impact can be challenging to estimate, as it depends on the type of imbalance, the parental origin of the affected allele, its size and genomic content. As a result, a genotype-phenotype correlation of 11p15.5 alterations is still missing, at least for CNVs affecting only parts of the IC1 or IC2. By comprehensively summarising all published CNVs within 11p15.5 and the available clinical data of their carriers, we aim to further delineate a correlation of these disturbances with BWS and SRS features. In fact, consistent correlations could be delineated only for duplications including either both the telomeric and centromeric regions or complete gains of one of them. In contrast, CNVs encompassing only parts of these regions lead to heterogeneous phenotypes. In summary, our literature review provides support for pathogenicity assessment of CNVs in 11p15.5 as basis for genetic counselling. However, this dataset underlines the need for further research to enlighten the molecular complexity of this region and to better understand the regulation of genomic imprinting mechanisms in 11p15.5.

This schematic illustrates the genetic, molecular, and clinical consequences of ESAM loss-of-function variants identified in two unrelated Turkish families. Family 1 harbors a splice-site variant (c.451 + 5G>C) predicted to cause aberrant splicing between exons 3 and 4, leading to defective mRNA processing and loss of functional ESAM protein. Family 2 carries a nonsense variant (c.605 T>G; p.Leu202Ter) that introduces a premature stop codon within the second immunoglobulin-like domain, resulting in a truncated protein and expected nonsense-mediated mRNA decay (NMD). Both variants abolish ESAM's membrane anchoring and disrupt endothelial junctional cohesion. Clinically, affected individuals present with a distinct neurovascular phenotype characterized by intrauterine or perinatal intracranial hemorrhage, ventriculomegaly, microcephaly, spastic quadriparesis, and congenital cataracts. The lower panel summarizes the pathophysiological cascade: (1) hemorrhagic stroke resulting from vascular fragility, (2) blood-brain barrier (BBB) disruption due to tight junction dysfunction and increased transcytosis, and (3) impaired vascular network formation caused by defective endothelial tubulogenesis. Collectively, these findings establish ESAM deficiency as a congenital tight-junctionopathy linking molecular endothelial defects to severe neurodevelopmental impairment.