BACKGROUND:Anophthalmia/microphthalmia (A/M) is a severe congenital ocular malformation characterized by the complete absence or small size of the eye bulb. Interpreting copy number variations (CNVs) in A/M is challenged by variable genotype-phenotype correlations and reduced penetrance. This study investigated the genetic etiology of A/M-associated CNVs. METHODS:Genomic profiling was performed on four unrelated families presenting with ocular anomalies or harboring A/M-susceptible CNVs. Variants were evaluated by integrating American College of Medical Genetics and Genomics (ACMG) guidelines with clinical phenotypes and familial segregation. RESULTS:An inherited 8.13 Mb deletion (8p23.3p23.1) in Patient 1 was excluded due to genotype-phenotype mismatch. Patients 2 and 3 harbored de novo pathogenic deletions involving OTX2 (14q22.3) and SOX2 (3q26.33), causing typical A/M. Case 4 revealed a 14q22.2q23.1 deletion encompassing OTX2 in a fetus and mother without ocular anomalies, consistent with the incomplete penetrance of OTX2-related microphthalmia. Thus, CNV-induced haploinsufficiency causes A/M with high phenotypic variability. CONCLUSION:Accurate CNV interpretation requires robust genotype-phenotype correlation and careful assessment of incomplete penetrance to prevent diagnostic pitfalls and improve genetic counseling.
ABSTRACT Background Esophageal squamous cell carcinoma (ESCC) showed remarkable male predominance, but the potential relevance of Y chromosome background remains unclear. This exploratory study investigated Y chromosome haplogroup distribution and its possible contribution to ESCC diagnostic modeling. Methods We recruited 517 male ESCC patients and 447 age‐matched healthy men from Sichuan, China. Y chromosomal short tandem repeats (Y‐STRs) were used to assess paternal lineage structure and exclude cryptic relations, and Y chromosomal single nucleotide polymorphisms (Y‐SNPs) were used to classify Y chromosome haplogroups. We analyzed the association between Y chromosome haplogroups and genetic susceptibility to ESCC by false discovery rate (FDR) correction and adjusted logistic regression. Repeated bootstrap‐Boruta and Boruta analyses were performed to evaluate feature selection stability of haplogroups. Nomogram model with and without O2a1b haplogroup was constructed using clinical variables, and compared by receiver operating characteristic (ROC), calibration, decision curve analyses, and DeLong test. Exploratory RNA‐seq was performed in tissue and blood samples from O2a1b‐positive and non‐O2a1b ESCC patients. Results Principal component analysis (PCA) and median‐joining tree showed substantial overlap between ESCC cases and controls. O2a1b had nominal positive association with ESCC, whereas O1b1a showed a nominal negative association with ESCC. However, no haplogroup remained significant after FDR correction. In adjusted logistic regression, O2a1b remained significant with ESCC, but repeated bootstrap‐Boruta analysis showed low feature‐selection stability for O2a1b and O1b1a. The nomogram without haplogroup, composed of BMI, CEA, ALB, ALP, TBA, and NLR, achieved AUCs of 0.883 and 0.888 in the training and validation cohort, respectively. Adding O2a1b did not significantly improve the performance of the nomogram. RNA‐seq suggested potential involving pathways, such as “Hippo signaling pathway” and “focal adhesion signaling pathway.” Conclusion Y chromosome haplogroups were not recognized as robust markers for ESCC diagnosis in our cohort. Although these findings should be regarded as exploratory and hypothesis‐generating, this study undermined the potential value of Y chromosome haplogroups and paternal lineage in male ESCC susceptibility. Further validation in larger independent cohorts is required.
ABSTRACT Background Dyskeratosis congenita (DKC) is typically characterized by the triad of abnormal cutaneous pigmentation, nail dystrophy, and oral mucosal leukoplakia. Progressive bone marrow failure develops in over 80% of cases and constitutes the leading cause of early mortality. Pathogenic variants in DKC1 have been associated with a high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors. The DKC1 missense variant, c.5C>T, leading to p.(Ala2Val), has been reported in families affected with dyskeratosis congenita. However, due to lack of functional analysis, it remains a variant of uncertain significance (VUS). Here, we performed functional analysis of the DKC1 gene product to investigate the pathophysiology of DKC1‐related dyskeratosis congenita. Methods We performed co‐localization studies of HEK293T cells transfected with GFP‐tagged constructs encoding either a wild‐type (WT) or p.(Ala2Val) human DKC1 protein, along with Liquid Chromatography Mass Spectrometry (LCMS) of immunoprecipitated (IP) WT or p.(Ala2Val) DKC1 protein to study post‐translation modification status. Results We have shown that p.(Ala2Val) DKC1 leads to mis‐localization of the protein from the nucleolus to the nucleoplasm. Also, LCMS showed that N‐terminal methionine cleavage occurs for both, but N‐acetylation occurs for WT but not for p.(Ala2Val) DKC1. Conclusion The mis‐localization and altered post‐translational modification of p.(Ala2Val) DKC1 provides functional evidence to clinical laboratories to reclassify p.(Ala2Val) variant as “pathogenic” as per American College of Medical Genetics (ACMG) variant interpretation guidelines.
ABSTRACT Introduction Type VIII 3‐methylglutaconic aciduria (MGCA8) is a neurodegenerative disorder which involves biallelic pathogenic variants of HTRA2. This gene encodes a mitochondrial serine protease responsible for apoptosis regulation and mitochondrial proteins' quality. Clinical manifestations include dysfunctional muscle tone, movement disorder, severe encephalopathy, epileptic seizures, dysautonomia, feeding difficulty, intermittent neutropenia, bradycardia, and recurrent apneas, often progressing into respiratory failure. Case Report We describe a newborn presenting with abnormal muscle tone, progressive dystonic movements, recurrent apneas, feeding difficulties, and epileptic seizures. Biochemical analysis revealed a markedly elevated urinary 3‐methylglutaconic acid, and genetic test identified biallelic pathogenic variant in HTRA2. Brain MRI revealed progressive brain atrophy, thalamic hypoplasia, and ventriculomegaly. EEG recordings found organizational abnormalities that turned into epileptic spasms. Despite intensive care, the patient suffered rapid neurological decline and died following a prolonged apnea episode. Thereafter the family had another infant diagnosed with the same biallelic pathogenic variant in HTRA2, that died a few days after birth due to respiratory failure. Discussion MGCA8 is a lethal condition characterized by loss‐of‐function biallelic mutations in HTRA2, which lead to mitochondrial dysfunction and altered apoptosis regulation, especially in the brain. High levels of 3‐methylglutaconic acid in urine are one important early diagnostic marker, when associated with a consistent clinical phenotype. Our report contributes to the limited existing case series and provides a detailed characterization of the EEG findings associated with this rare condition.
ABSTRACT Background Muscle‐Eye‐Brain disease (MEB) is a rare autosomal recessive dystroglycanopathy caused by defective glycosylation of α‐dystroglycan, leading to a multisystem disorder involving the central nervous system, skeletal muscle, and eyes. It represents an important cause of developmental and epileptic encephalopathy, with variable clinical severity and genetic heterogeneity, most commonly associated with variants in the POMGNT1 gene. Methods Clinical, neurophysiological, neuroimaging, histopathological, and genetic investigations were performed, including targeted next‐generation sequencing for congenital muscular dystrophy‐associated genes. Results The patient presented with early‐onset hypotonia, global developmental delay, progressive motor regression, intellectual disability, and ocular abnormalities. Epilepsy onset occurred in childhood and evolved into drug‐resistant epilepsy with status epilepticus in adulthood. Brain MRI revealed lissencephaly, ventriculomegaly, and brainstem and cerebellar hypoplasia. EEG demonstrated features consistent with epileptic encephalopathy. Genetic testing identified compound heterozygosity for the POMGNT1 variants c.1282C>T, p.(Gln428*) and c.793C>T, p.(Arg265Cys). Seizure control was eventually achieved with polytherapy including four antiseizure medications. Conclusion This case expands the genotypic and phenotypic spectrum of POMGNT1‐related MEB, highlighting the potential for severe epilepsy and status epilepticus in adulthood. It also underscores the importance of long‐term clinical follow‐up and suggests that aggressive antiseizure treatment may achieve seizure control even in advanced stages of the disease.
ABSTRACT Objective The objective of this study was to investigate the clinical features and genetic variation of a patient with monogenic nonsyndromic obesity caused by melanocortin 4 receptor (MC4R) gene variation. Additionally, this study aims to provide a reference for the diagnosis of the disease. Methods A monogenic non syndromic obese patient who was admitted to Dongying People's Hospital in December 2024 was enrolled in the study. The clinical data and peripheral blood samples of the patient were collected. Whole‐exome sequencing was utilized to identify gene variants. Subsequently, bioinformatic analysis was performed on the candidate variants detected in the patient. The pathogenicity of the variant was evaluated in accordance with the Standards and Guidelines for the Classification of Genetic Variants, which were formulated by the American College of Medical Genetics and Genomics (ACMG). A comprehensive database was meticulously curated to encompass all previously documented monogenic non syndromic cases. A retrospective analysis was then conducted to systematically summarize the phenotypic and pathogenic variation spectrum of the MC4R gene. A comprehensive review of the extant literature on cellular and molecular genetics was conducted, with the objective of elucidating the discrepancies between the mutation location of the MC4R gene and its clinical phenotype. Results The results of the patient's case reveal that the subject is a 10‐year‐2‐month‐old female who exhibits the clinical manifestations of severe obesity, hyperinsulinemia, and accelerated puberty development. Whole‐exome sequencing revealed a missense mutation c.185A > G (p.Asn62Ser) in the MC4R gene. According to the ACMG guidelines, the variant was designated as pathogenic (PM2_Supporting + PM3_Supporting + PS4_Supporting + PS3_Moderate + PP1_Strong + PP3_Supporting). A comprehensive literature search yielded a total of 64 children with obesity caused by MC4R mutation. Regardless of the location of the mutation, whether in the transmembrane region or the topological region, no statistically significant differences were observed in age (months), gender, BMI, BMISDS, acanthosis nigricans, hyperinsulin, hyperappetite, and underlying diseases between the two groups. Interaction analysis revealed a significant modification effect of underlying disease status on the association between mutation location and BMI (P for interaction = 0.002–0.069). Among children without underlying diseases, topological region mutations were associated with higher BMI (β = 8.52, 95% CI: −3.20–20.24), whereas among those with underlying diseases, the effect was reversed (β = −9.73, 95% CI: −21.42–1.96), indicating opposite directions of effect across subgroups. Conclusion The present study has demonstrated that MC4R gene missense variants are among the most prevalent genetic factors contributing to monogenic nonsyndromic obesity. For children with early‐onset severe obesity, accelerated puberty, and hyperinsulinemia, the consideration of monogenic nonsyndromic obesity is imperative, and genetic testing should be utilized to confirm the diagnosis expeditiously. In the context of pediatric obese patients with underlying diseases, the effect of different mutation positions on BMI varies. These findings also expand the spectrum of MC4R variants.
ABSTRACT Background Multifocal sporadic venous malformations (MSVM) are a rare and severe subtype of venous malformations (VMs). Although somatic mutations in the TEK gene are frequently implicated in VMs, the clinical and molecular significance of harboring two distinct somatic mutations within a single lesion remains poorly understood. Methods DNA was extracted from both the lesion and peripheral blood, followed by whole‐exome sequencing (WES) and structural modeling of the TIE2 protein. Results The proband, a 6‐year‐old Chinese boy, presented at birth with soft‐tissue swelling of the hands and occipital region, which progressively involved the tongue, neck, trunk, extremities, and external genitalia. Imaging demonstrated extensive venous ectasia infiltrating subcutaneous and muscular layers. Despite 20 sessions of sclerotherapy, the lesions continued to progress and showed a strong tendency for recurrence. WES of the lesion revealed two pathogenic somatic mutations in the TEK gene: c.2740C>T (p.L914F) and c.2545C>T (p.R849W), which weren't detected in peripheral blood. Structural modeling suggested no major global conformational changes but showed possible local structural differences within the kinase domain. The double‐mutant variant exhibited predicted enhanced hydrogen bonding at the mutation sites, potentially contributing to local structural rearrangements and altered conformational stability. Conclusion This report describes a previously unreported case of dual somatic TEK mutations in MSVM. The findings expand the mutational spectrum of TEK‐related VMs and underscore the importance of lesion‐based genetic testing in complex cases.
ABSTRACT Background This study aims to present novel compound heterozygous PROC gene variants in a fetus. These variants cause protein C deficiency‐associated thrombophilia and are accompanied by prenatal ocular anomalies in the affected fetus. Methods A fetus presenting with prenatal ocular ultrasound anomalies was enrolled for genetic prenatal diagnosis. Trio whole‐exome sequencing (WES) was performed on the fetus and parental samples to explore the genetic etiology. Sanger sequencing was subsequently applied to verify the identified genetic variants. Results WES result revealed two likely pathogenic compound heterozygous variants NM_000312.4: c.[378G>A(p.W126*)]; [658C>T(p.R220W)] in PROC gene in the fetus, which were inherited from the parents, respectively. Notably, a likely pathogenic homozygous variant of NM_176824.3:c.728G>A(p.C243Y) in BBS7 gene, and a heterozygous variant of NM_012193.4:c.112G>A(p.G38R) in FZD4 gene, as well as a pathogenic heterozygous variant of NM_000435.3:c.1630C>T(p.R544C) in NOTCH3 gene were observed in the mother, which may explain her clinical abnormalities. The maternal BBS7 variant was transmitted to the fetus, whereas the FZD4 and NOTCH3 variants were not detected in the proband. The father exhibited a clinical phenotype of cleft lip and palate, but no corresponding pathogenic genetic variants were identified. Conclusion This study first reports two rare compound heterozygous PROC variants in a Chinese fetus, which expands the mutational spectrum of protein C deficiency‐related thrombophilia in the Chinese population. Furthermore, our findings highlight the robust clinical application value of trio‐WES in the etiological diagnosis of complex prenatal genetic disorders.
ABSTRACT Background Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder typically inherited in an autosomal recessive pattern. Pseudo‐dominant inheritance is exceptionally uncommon and remains poorly characterized in PCD. Methods We conducted a clinical and genetic study of a non‐consanguineous Chinese PCD pedigree with four affected individuals across two generations. Whole exome sequencing and Sanger sequencing were performed to identify pathogenic variants. Results Two variants in DNAAF1 , c.1930A>T (p.Arg644Ter) and c.1022_1023del (p.Gln341ArgfsTer10), were identified and shown to co‐segregate with the disease in a pseudo‐dominant pattern. The proband, her brother, and her two naturally conceived sons were all affected, with her parents and husband being unaffected carriers. Transmission electron microscopy revealed absence of both outer and inner dynein arms, and high‐speed video analysis demonstrated immotile or severely reduced ciliary beating. Intrafamilial phenotypic variability was notable, including distinct laterality defects (situs inversus, heterotaxy, and situs solitus) and varying degrees of pulmonary involvement. Conclusion Our report provides the first description of pseudo‐dominant inheritance in PCD and expands the knowledge of the disease by offering detailed clinical and ciliary phenotyping.
ABSTRACT Background The synonymous DLG4 variant is annotated with conflicting pathogenicity interpretations, and its molecular mechanism remains uncharacterized. Paternal germline mosaicism has been inferred but never molecularly confirmed in DLG4 ‐related synaptopathy. Objective To functionally validate the pathogenicity of the synonymous DLG4 variant NM_001365.4:c.771G>A (p.Ala257=), and elucidate its inheritance mechanism in a proband with neurodevelopmental delay. Methods We performed trio‐whole‐exome sequencing in a proband with neurodevelopmental delay. The pathogenicity of the identified variant was assessed using bioinformatic predictors and validated through Sanger sequencing, RNA sequencing, and RT‐PCR. The inheritance pattern was investigated via high‐depth amplicon sequencing of paternal sperm DNA. Results The synonymous DLG4 c.771G>A variant (absent in gnomAD) induced complete exon 9 skipping, resulting in a frameshift and premature termination codon. The variant was present at 3.83% variant allele frequency in paternal sperm, establishing paternal germline mosaicism as the origin. Conclusion Our study resolves conflicting interpretations of the DLG4 c.771G>A variant by demonstrating its pathogenic splice‐disrupting effect. To our knowledge, this provides the first molecular confirmation of paternal germline mosaicism in DLG4 ‐related synaptopathy. We note that maternal germline mosaicism was not assessed. These findings underscore the dual necessity of functional analysis for synonymous variants and sensitive mosaicism detection for accurate genetic counseling.
ABSTRACT Background Infantile‐onset cardiomyopathy due to mitochondrial dysfunction is a severe condition frequently associated with poor prognosis. Biallelic pathogenic variants in ELAC2 , an essential mitochondrial tRNA processing gene, have been implicated in this phenotype. This study investigates the clinical and genetic spectrum of ELAC2 ‐related disease in a national cohort from Kuwait. Methods We conducted a retrospective cohort study using data from the Kuwait Medical Genetics Center registry, including individuals with genetically confirmed or clinically suspected ELAC2 ‐related cardiomyopathy. Clinical, metabolic, and molecular data were reviewed. Exome sequencing or targeted mutation testing was performed in affected individuals and at‐risk family members. Results A total of 34 individuals from 23 consanguineous families were identified, of whom 30 were genetically confirmed to harbor the homozygous ELAC2 founder variant c.460T>C; p.(Phe154Leu). All individuals presented in infancy with severe cardiomyopathy and refractory lactic acidosis. Neurological involvement was observed in 39% of cases. The majority exhibited hypertrophic cardiomyopathy, with variable dilated features and pericardial effusion. The disease course was fatal in all, with most patients dying in infancy. Conclusion This is the largest single‐country cohort reported to date with ELAC2 ‐related mitochondrial cardiomyopathy, raising the global case total to over 70. The uniform presence of the Phe154Leu variant across unrelated Bedouin families highlights a strong founder effect. Given the rapid disease progression and high mortality, we recommend targeted ELAC2 screening in infants with idiopathic cardiomyopathy and persistent lactic acidosis, particularly in consanguineous populations. Premarital carrier testing and early family counseling should be prioritized to support preventive strategies.
ABSTRACT Background Alport syndrome (AS) is a multisystem hereditary disorder characterized by persistent hematuria, progressive renal insufficiency, sensorineural hearing loss, and ocular abnormalities. Its pathogenesis is mainly due to mutations in COL4A3, COL4A4, or COL4A5 genes encoding type IV collagen α chains, leading to glomerular dysfunction and end‐stage renal disease. A systematic evaluation of its global research landscape is lacking, and bibliometric analysis can fill this gap. Methods A comprehensive bibliometric analysis was conducted using Biblioshiny, VOSviewer, and CiteSpace. Data were extracted from the Web of Science Core Collection (2000–2025), with 1205 valid publications included. Multiple dimensions including annual output, citations, co‐authorship, and keywords were analyzed. Results Bibliometric analysis showed that AS‐related annual publications had a consistent upward trend from 2000 to 2025. The 1205 included publications accumulated 34,314 citations, with the most cited being R. C. Wiggins' 2007 original study (622 citations). Co‐authorship analysis identified Judy Savige as the most prolific author and the United States as the leading contributing country. Co‐citation analysis mapped the field's intellectual structure, and keywords included “natural history,” “IV collagen,” and “identification” besides core terms “Alport syndrome” and “mutations”. Conclusion Global interest in AS research has increased significantly. With academic exchanges and international cooperation, its pathogenesis mechanisms are gradually clarified. This bibliometric analysis identifies research hotspots and guides future directions, providing references for related research and clinical practice.
ABSTRACT Purpose Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by resistance to adrenocorticotropic hormone (ACTH), leading to isolated glucocorticoid deficiency. This study aims to identify the genetic basis of FGD in a Chinese patient and investigate the functional consequences of the detected MC2R mutations. Methods Whole‐exome sequencing was performed to detect pathogenic variants in the MC2R gene. The effects of these mutations on MC2R mRNA and protein levels were analyzed using qPCR and immunoblotting. Additionally, a luciferase reporter assay was conducted to evaluate ACTH‐induced cyclic adenosine monophosphate (cAMP) signaling. Results The patient was found to carry compound heterozygous mutations in MC2R (p.Leu151Pro and p.Glu28*), inherited from the father and mother, respectively. Functional studies revealed that these mutations led to reduced MC2R mRNA and protein expression. Furthermore, the luciferase assay demonstrated that these variants attenuated ACTH‐induced cAMP signaling. Conclusion Novel pathogenic mutations in the MC2R gene were identified, and their functional impact was characterized. These findings provide insights into the molecular mechanisms underlying FGD and contribute to the expanding genetic spectrum of the disease.
ABSTRACT Background Isolated hypogonadotropic hypogonadism (IHH) is a rare endocrine disorder caused by genes such as ANOSI (OMIM*300836), FGFR1 (OMIM*136350), PROK2 (OMIM*607002) and PROKR2 (OMIM*607123) (etc.), leading to downstream dysfunction of pituitary gonadotropin secretion and subsequent impairment of gonadal function. Clinical manifestations include incomplete or partial puberty and infertility. Methods and Results In this study, whole‐genome sequencing of a female patient with HH identified a novel 5′ splice site variant c.285 + 772 T>G in the deep intron of PROK2 (NM_001126128.2). In vitro minigene validation revealed abnormal splicing of this variant, with 69 base pairs retained in intron 3, ultimately leading to changes in protein length, which may lead to changes in protein structure. According to the American College of Medical Genetics and Genomics (ACMG) pathogenicity classification, this variant is rated as likely pathogenic variant (LP). Conclusion PROK2 variants can lead to HH and we report a case with a novel splice site variant that has been confirmed to lead to the retention of 69 base pairs in intron 3 during RNA splicing.
ABSTRACT Introduction Loss‐of‐function variants in NONO cause an X‐linked syndromic neurodevelopmental disorder (MRXS34), characterized by developmental delay, corpus callosum abnormalities, dysmorphic features, feeding difficulties, and congenital heart disease, most commonly left ventricular noncompaction cardiomyopathy (LVNC). Long‐term outcome data remain limited. Methods A 14‐year‐old boy with LVNC and syndromic neurodevelopmental features underwent exome sequencing and subsequently NONO transcript analysis. A literature search was conducted using the terms “NONO variant” and “NONO mutation”. Results Exome sequencing identified a hemizygous NONO variant, c.348G>A, absent from population databases. This silent mutation was predicted in silico to cause exon 4 skipping, resulting in a frameshift and a premature termination codon p.(Asn52Argfs*31). This prediction was confirmed by RT‐PCR, and it was demonstrated that the aberrant transcript was subject to nonsense‐mediated mRNA decay. The patient displayed the characteristic NONO‐associated phenotype with rapid cardiac deterioration requiring pulsatile left ventricular assist device implantation at 1 year of age, and orthotopic heart transplantation at 2 years of age. At 14 years, graft function remains stable. An emergency hemicolectomy due to volvulus was performed at 12 years of age. A literature search identified 32 live‐born patients and 11 fetuses with NONO loss‐of‐function mutations. Intellectual disability, particularly affecting language development, LVNC, a recognizable facial phenotype, dystrophy, and lean habitus were nearly invariantly present. Conclusion This report further emphasizes the core phenotype caused by NONO loss‐of‐function, describes the second individual with heart transplantation, and indicates an underrecognized prevalence of gastrointestinal features.
ABSTRACT Background Genetic causes of congenital heart disease (CHD) are often underrecognized, though precision phenotyping may improve screening for genetic disorders. We demonstrate how body region dysmorphology predicts genetic diagnoses associated with CHD. Methods We used a test‐negative case–control study of CHD infants undergoing standardized genetics evaluations. We investigated correlations between body region dysmorphology (BRD) and CHD classes and developed novel models for predicting genetic diagnoses, including cytogenetic/monogenic disorders identified by genetic testing. Results In 243/1008 patients with genetic diagnoses (24.1%), we found novel correlations between BRDs and CHD classes. Periorbital, maxilla/midface, ear, and mandible BRDs correlated with conotruncal CHD with genetic diagnoses (25.5%); left ventricular outflow tract CHD presented with few BRDs despite genetic diagnoses identified (18.5%). Septal and right ventricular outflow tract CHD had a wider spectrum of BRDs. Multivariable modeling identified multiple BRDs predicting genetic diagnoses, including of the face (OR = 2.57), forehead (OR = 2.55), neck (OR = 2.24), periorbital (OR = 1.57), and hands/feet (OR = 1.90) regions, after adjusting for extracardiac anomalies (OR = 3.65), CHD class (p = 0.02), and male sex (OR = 0.69). The BRD model had acceptable utility assessed by decision curve analysis. Face/forehead/neck BRDs predicted cytogenetic and monogenic diagnoses (ORs ranging 2.2–2.5), though BRDs of hands/feet associated with cytogenetic disorders (OR = 2.22). Males were less likely to have cytogenetic diagnoses compared to females (OR = 0.59), suggesting potential sex‐specific differences. Conclusions This is a novel investigation of body region dysmorphology patterns predictive of genetic diagnoses in CHD patients. Precision phenotyping can be an important part of care and allow clinicians to risk‐stratify young CHD patients suspected of having genetic disorders.
ABSTRACT Background Duchenne muscular dystrophy (DMD) is an X‐linked neuromuscular disorder caused by pathogenic variants in the DMD gene, which encodes dystrophin, a cytoskeletal protein linking intracellular actin to the extracellular matrix via the dystrophin‐associated protein complex and maintaining muscle fiber integrity. With the emergence of disease‐modifying therapies, early and accurate molecular diagnosis is increasingly important. Whole‐exome sequencing (WES) is widely used to evaluate unexplained hyperCKemia and distinguish DMD from other inherited neuromuscular disorders. Results WES identified a novel hemizygous frameshift variant in DMD (NM_004006.3:c.6050_6051del; p.Leu2017Profs*5) in a Taiwanese boy with markedly elevated creatine kinase levels (> 10,000 U/L) and clinical features consistent with DMD. The variant was classified as likely pathogenic according to ACMG criteria (PVS1, PS2, PP3). Comparative genomic analysis demonstrated strong evolutionary conservation at the variant site within the 16th spectrin‐like repeat (exon 42), with phastCons scores of 1 and phyloP scores of +2.925 and +1.015. AlphaFold‐based structural modeling suggested disruption of the three‐helix bundle architecture, while CHARMM‐based energy analysis suggested a potential destabilizing effect that appeared more consistent with previously reported pathogenic exon 42 frameshift variants than with benign missense variants at the same locus. Conclusions This is the first reported case of DMD associated with the novel frameshift variant c.6050_6051del (p.Leu2017Profs*5). Integrated genomic, evolutionary, and structural analyses support the likely pathogenic interpretation of this variant. This study expands the mutational spectrum of DMD and highlights the value of combining WES with structure‐informed approaches for variant interpretation. These findings provide preliminary structural insights into the potential effects of the identified variant and highlight the possible utility of structure‐informed variant interpretation in the absence of functional assays.
BACKGROUND:Inherited forms of cataract are a clinically important and genetically heterogeneous cause of visual impairment, usually present at an early age. Both syndromic and non-syndromic congenital cataracts exhibit all modes of inheritance and may occur in association with various ocular or systemic abnormalities. Early diagnosis and treatment are crucial for the visual prognosis. METHODS:We applied next-generation sequencing (NGS) of clinical exome for identification of the disease-causing variants in a group of seven Bulgarian patients with syndromic and non-syndromic cataracts, accompanied by glaucoma with variable anterior segment defects and other ocular phenotypes. RESULTS:Systematic filtering pipelines coupled with copy number variation analysis and segregation studies led to the identification of four pathogenic/likely pathogenic changes and two variants of uncertain significance (VUS), three of which were newly found. Candidate disease-causing variants in the CRYAA, CRYBB1, MYH9, RP2, CLNC1, and CACNA1S genes were found, which allowed the establishment of a precise genetic diagnosis of all of the studied pedigrees. CONCLUSION:Our results confirm the usefulness of a targeted NGS approach based on clinical exome analysis as a comprehensive genetic diagnostic tool for syndromic and isolated cataracts with a significant impact on patient counseling.
ABSTRACT Background This study characterizes the clinical and genetic features of ABCA4 ‐associated inherited retinal diseases (IRDs) in eight unrelated probands from the three provinces of Northeast China. All patients harbored biallelic pathogenic ABCA4 variants, with detailed variant profiles provided in Table 2. Methods Eight unrelated Chinese pedigrees (31 individuals, including 8 probands and 23 family members) with ABCA4 ‐related IRDs. All participants underwent comprehensive ophthalmic examinations. Genetic variants were identified using a targeted next‐generation sequencing (NGS) panel for IRDs. For all candidate pathogenic variants, in silico pathogenicity predictions were performed using REVEL, PolyPhen‐2, MutationTaster, SIFT, and LRT (Likelihood Ratio Test). The pathogenicity of the variants was classified in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG), integrating computational evidence and segregation analysis. All candidate variants were validated by bidirectional Sanger sequencing, and co‐segregation analysis was performed in available family members. Results Sixteen ABCA4 variants were identified, including six novel potentially deleterious variants (three predicted loss‐of‐function). ACMG classifications comprised six pathogenic variants, eight likely pathogenic variants, and two variants of uncertain significance (VUS). Phenotypically, six probands presented with Stargardt disease type 1 (STGD1), one with early‐onset severe retinal dystrophy (EOSRD, compound heterozygous ABCA4 variants), and one with an unclassified IRD. The three provinces of Northeast China STGD1 patients displayed a higher proportion of mild‐severity variants yet presented with an earlier median onset age (10.6 years) and more severe visual impairment (77.2% with best‐corrected visual acuity < 0.1) when compared to global cohorts. However, this observation may reflect referral bias to a tertiary center and requires validation in larger, multi‐ethnic cohorts. Conclusions Targeted NGS identified six potentially novel ABCA4 variants in the Northeast Chinese population, including three predicted loss‐of‐function variants. This study reports a case of ABCA4 associated EOSRD, thereby broadening the documented ABCA4 variant spectrum in this population.
