ABSTRACT Background Dystroglycanopathies are a clinically and genetically heterogeneous group of muscular dystrophies caused by impaired glycosylation of α ‐dystroglycan, with variants in multiple genes, including CRPPA , which is associated with a broad spectrum ranging from congenital muscular dystrophy to limb‐girdle muscular dystrophy. Method The proband underwent whole exome sequencing, while Sanger sequencing was used for segregation analysis and oligonucleotide array‐CGH was performed to confirm the copy number variant. Results We report two siblings harboring an identical novel compound heterozygous CRPPA genotype, comprising a novel c.267G>C missense variant and a deletion encompassing exons 9–10. Despite sharing the same genotype, the siblings showed marked phenotypic variability. The female sibling developed childhood‐onset disease with proximal weakness involving both the upper and lower limbs, whereas the male sibling presented with late‐onset disease and weakness confined to the proximal lower limbs, accompanied by markedly discordant serum creatine kinase levels (1193 vs. 460 U/L). Conclusion These findings expand the mutational and clinical spectrum of CRPPA‐related dystroglycanopathy, highlight marked intrafamilial phenotypic variability, and emphasize the importance of integrated single‐nucleotide and copy number variant analysis in the genetic diagnosis of neuromuscular disorders.
ABSTRACT Background Rothmund‐Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, sparse hair, short stature, skeletal abnormalities, and an increased predisposition to malignancies. Pathogenic variants in the RECQL4 gene represent the most common genetic cause of RTS type 2. However, the full phenotypic spectrum, particularly regarding endocrine manifestations, remains incompletely understood. Objective To report novel compound heterozygous RECQL4 pathogenic variant in a Chinese patient, describe a previously unreported endocrine phenotype (gynecomastia), and provide a comprehensive review of the literature regarding the RECQL4 mutational spectrum and differential diagnosis. Methods A comprehensive clinical evaluation, including detailed physical examination, dermatoscopic assessment, and histopathological analysis, was performed. Whole‐exome and Sanger sequencing were conducted to identify the causative variants. A literature review was additionally performed to contextualize the clinical and genetic findings. Results A 14‐year‐old boy presented with classical poikiloderma, short stature, and an unreported feature of gynecomastia associated with low testosterone levels. Genetic testing identified compound heterozygous variants in RECQL4 : a known nonsense variant c.2290C>T (p.Glu764*) and a novel frameshift variant c.2053del (p.Asp685Thrfs*5). Our literature review further delineated the differential diagnosis of poikiloderma among related genodermatoses and highlighted the systemic impact of RECQL4 dysfunction. Conclusion The identification of the novel c.2053del variant broadens the known mutational landscape of RECQL4 . Furthermore, the integration of our newly observed endocrine phenotype with a literature review underscores the necessity of multidisciplinary evaluation—including endocrinological, orthopedic, and audiological assessments—in the comprehensive management of RTS.
ABSTRACT Background Type 2 diabetes mellitus (T2DM) exhibits strong familial aggregation. This study aimed to identify potential pathogenic genes and mutation sites in a Chinese pedigree with a high prevalence of T2DM. Methods A multigenerational family with 20 members, including 5 diagnosed with T2DM, was enrolled. The proband was a second‐generation female with a 10‐year disease history. Peripheral blood was collected, genomic DNA was extracted from blood cells, and whole exome sequencing was performed. Bioinformatic analysis, including KEGG pathway mapping, was used to screen candidate pathogenic variants. Results Sequencing revealed 485 DNA variants, which were filtered to 16 high‐priority mutations (15 SNPs and 1 Indel). Through literature review and functional pathway analysis, two heterozygous mutations—EPHX3 rs760409070 [c.778G>A, p.Glu260Lys] and FHOD1 rs142023201 [c.1493A>G, p.Asn498Ser]—were identified as candidate pathogenic variants. These two mutations were consistently present in all affected family members. Conclusion The EPHX3 rs760409070 and FHOD1 rs142023201 mutations are likely contributing genetic factors to T2DM in this pedigree. Based on bioinformatic analysis, we hypothesize that these mutations may promote diabetes pathogenesis by reducing peripheral insulin sensitivity, impairing glucose uptake, suppressing glycogen synthesis, and enhancing gluconeogenesis.
ABSTRACT Background Global developmental delay (GDD) and intellectual disability (ID) are neurodevelopmental conditions with significant phenotypic and genetic heterogeneity. EEF1D (OMIM* 130592) has recently been identified as a gene of interest in neurodevelopmental disorders. Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language (NEDTCHAL) (OMIM #621150) is caused by homozygous or compound heterozygous disease‐causing variants in the EEF1D . Methods We performed whole exome sequencing (WES) on an Iranian sibling presenting with global developmental delay, intellectual disability, microcephaly, and failure to thrive. Bioinformatic analysis and Sanger sequencing were used to validate and characterize the identified variant. Results A novel homozygous splicing variant in EEF1D (c.1489‐26_1493del) was identified in both affected individuals. The variant is predicted to disrupt splicing and cause a frameshift deletion. Previous studies have implicated biallelic EEF1D variants in neurodevelopmental disorders, and this report is the first from the Iranian population and the seventh family to be reported worldwide with this rare condition. Conclusion This report provides further evidence for the association between EEF1D variants and neurodevelopmental disorders, expanding the phenotypic spectrum of EEF1D ‐related conditions. It reinforces the importance of recognizing EEF1D as a key gene involved in developmental delay and intellectual disability.
ABSTRACT Background This study aimed to evaluate the association between genetic variants and haplotypes of ERAP1 and clinical outcomes in cervical cancer patients, utilizing data from the TCGA‐CESC and a cohort of Brazilian patients. Methods ERAP1 variants and haplotypes were evaluated in two distinct cohorts: whole‐exome sequencing (WES) data from 173 cervical cancer cases in the TCGA‐CESC dataset, and Sanger sequencing data from 52 Brazilian cervical cancer patients. The TCGA‐CESC data were employed for in silico analysis to identify significant ERAP1 variants and haplotypes, which were subsequently evaluated in Brazilian cervical cancer samples. The Tumor IMmune Estimation Resource (TIMER) tool was used to assess the association between ERAP1 expression and immune cell infiltration. Results Haplotype analysis of ERAP1 in the TCGA‐CESC dataset revealed that H005 (rs26653—rs2287987—rs30187—rs10050860—rs17482078—rs27044) and H023 (rs26653—rs27895—rs30187—rs27044) haplotypes were significantly associated with poorer survival outcomes. Homozygosity for H005 and the presence of H023 were strongly associated with both overall survival (OS) (HR = 9.591, p = 0.00384; HR = 10.183, p = 0.02862, respectively) and disease‐specific survival (DSS) (HR = 12.851, p = 0.00162; HR = 15.183, p = 0.01191, respectively). TCGA‐CESC data showed that homozygosity for rs2287987 (p.Met349Val) was associated with an increased risk of death in both overall survival (OS) (HR = 11.043, p = 0.00376) and disease‐specific survival (DSS) (HR = 13.833, p = 0.00255), whereas rs30187 (p.Lys528Arg) demonstrated a protective effect for DSS, reducing mortality risk in both heterozygous (HR = 0.374, p = 0.04055) and homozygous (HR = 0.346, p = 0.03845) forms. However, although these variants were individually associated with survival outcomes in the dataset, this association was not retained in the multivariate analysis, suggesting that these variants may not have an independent prognostic effect. Similarly, no associations were found for these variants in the Brazilian cervical cancer cohort, suggesting that the impact of these variants on the prognosis of cervical cancer patients may be primarily influenced by the combination of variants. Furthermore, ERAP1 expression levels were positively correlated with CD8 + T cell infiltration (correlation coefficient = 0.264, p = 0.00000960), which was associated with improved survival outcomes (HR = 0.006, p = 0.049). Conclusion ERAP1 haplotype H005 homozygosity and the presence of H023 were linked to poorer prognosis, indicating their potential as prognostic biomarkers in cervical cancer patients. Individually, the rs2287987 variant showed a potential association with worse outcomes in the TCGA dataset; however, this finding was not replicated among Brazilian patients, suggesting the potential role of these variants when considered as haplotypes in the function of ERAP1 . Additionally, the protective role of CD8+ T cell infiltration highlights its relevance as a possible therapeutic target for improving survival in cervical cancer patients.
