Compound Heterozygous ATM Variants Cause Adolescent‐Onset Cerebellar and Extrapyramidal Disease Without Telangiectasia in a Consanguineous Pakistani Family

Biallelic EZH1 Nonsense Novel Variant in Two Siblings with Neurodevelopmental Disorder and Central Precocious Puberty: A Case Report from a Consanguineous Saudi Family

This study expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.

“Severe intellectual disability with cardiac and dermatologic involvement due to homozygous METTL23 frameshift mutation: a case report of two Turkish sisters”

Case Report: Clinical and molecular genetic analysis of a patient with coexisting complete androgen insensitivity syndrome and neurofibromatosis type 1 and 15pstk + polymorphism

To report a pediatric patient with coexisting complete androgen insensitivity syndrome (CAIS), neurofibromatosis type 1 (NF1), and 15pstk + polymorphism, and to analyze its clinical phenotypes and molecular genetic characteristics. Clinical data of a 7-year-and-11-month-old patient with female social gender were retrospectively analyzed. Pathogenic gene variants were identified by whole-exome sequencing (WES), pedigree verification was performed by Sanger sequencing, and variant pathogenicity was evaluated using bioinformatics tools. The patient exhibited typical phenotypes of both diseases, accompanied by unique features, including epicanthal folds, webbed neck, broad great toes and thumbs. WES identified a maternally inherited hemizygous missense variant in the AR gene (c.2599G > A, p.Val867Met) and a de novo heterozygous missense variant in the NF1 gene (c.5488C > T, p.Arg1830Cys). This is the first report of concurrent CAIS and NF1, which enriches and expands the genotypic and phenotypic spectra of both disorders.

Homozygous Nonsense DSP Variants Selectively Affecting Desmoplakin I Cause Carvajal Syndrome in a Consanguineous Arabian Family with Four Affected Female Siblings

Introduction: Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by fibrofatty replacement of the myocardium and is associated with heart failure and sudden cardiac death. It can involve either ventricle, including left-dominant forms defined partly by genetic findings. Methods: We investigated a consanguineous family with four affected daughters presenting with ACM, epidermolytic palmoplantar keratoderma, and woolly hair. The two eldest siblings died suddenly during childhood. The remaining two affected siblings underwent genetic analysis using autozygosity mapping and whole-exome sequencing, followed by segregation analysis. Results: Autozygosity mapping identified a shared identity-by-descent (IBD) interval at the DSP locus on chromosome 6. Exome sequencing revealed a novel homozygous nonsense variant (c.4297C>T; p.Gln1433*; rs1554108283) in exon 23 of DSP. This variant introduces a premature termination codon within the region specific to transcript variant 1, sparing transcript variant 2. Both parents were heterozygous carriers. Cardiac imaging in the affected siblings demonstrated biventricular involvement, including left ventricular systolic dysfunction and right ventricular dilatation. Skin biopsy in one patient confirmed epidermolytic palmoplantar keratoderma. Conclusions: We describe a novel homozygous nonsense variant in the transcript 1-specific region of DSP causing Carvajal syndrome, characterized by severe biventricular ACM, epidermolytic palmoplantar keratoderma, and woolly hair, in a consanguineous Arabian family with four affected sisters.

Identification of a novel and a recurrent CDC45 variant in a Chinese family with Meier-Gorlin syndrome 7 and a literature review

Meier-Gorlin syndrome 7 (MGORS7) is a rare autosomal recessive disorder characterized by primordial dwarfism, craniosynostosis, and patellar aplasia, caused by pathogenic variants of CDC45 . Here, we report a Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments. Clinical and radiological data were collected. Whole-genome sequencing and Sanger sequencing were performed to identify and validate the causative variants. Their functional effects were investigated using an exon-trapping assay, and a literature review of previously reported MGORS7 cases was conducted. Genetic analysis identified two compound heterozygous CDC45 variants: c.1416C>T (p.H472=) and c.1559+2T>A, which are a recurrent variant in the East Asian population and a novel variant, respectively. Our exon-trapping assay indicated that c.1559+2T>A induced aberrant splicing, generating transcripts predicted to undergo nonsense-mediated mRNA decay. Additionally, growth hormone therapy was initiated in our patient, with a noted improvement in growth parameters in the initial assessment and without immediate complications. The literature review identified a total of 32 CDC45 variants in 29 patients with MGORS7, who showed high heterogeneity in clinical phenotypes. Our study further expanded the mutational spectrum of CDC45 and provided a preliminary clinical observation suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.

SEPTIN9 R106W in a Chinese family with hereditary neuralgic amyotrophy: phenotypic heterogeneity and rehabilitation in a pediatric case

Introduction Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant recurrent focal neuropathy characterized by acute episodes of severe neuropathic pain followed by muscle weakness and atrophy, most commonly affecting the brachial plexus. Pathogenic variants in SEPTIN9 with c.316C>T (p. Arg106Trp; NM_001113491.2) missense mutation corresponding to c.262C>T (p. Arg88Trp; NM_006640.4) constituting a recurrent hotspot that accounts for approximately 55% of HNA families in which a pathogenic SEPTIN9 variant can be identified. Although well documented in Caucasian and some Asian populations, reports in the Chinese population remain scarce, and the full phenotypic spectrum and optimal management strategy are incompletely defined. Methods Pathogenic variants were identified by whole-exome sequencing (WES) of the proband and confirmed by Sanger sequencing in available relatives. Results We report a three-generation Chinese pedigree harboring the SEPTIN9 R106W mutation. The proband, a 34-year-old female, experienced a painless, self-limiting left upper limb weakness at age nine that resolved spontaneously after 6 months, following a 20-year asymptomatic period. She relapsed postpartum at age 29 with bilateral upper limb pain, weakness, and atrophy, resulting in residual neurological deficits. Her 5-year-old daughter presented with infection-triggered classic childhood HNA, exhibiting distinctive facial features (hypertelorism, epicanthal folds, short palpebral fissures, microstomia, and neck webbing), scapular winging, and severe right upper-limb motor impairment. The child showed functional improvement temporally associated with treatment following corticosteroid pulse therapy, neurotrophic support, and a structured, phased rehabilitation protocol. The proband’s father had atypical hand numbness and tremor in young adulthood and later died of systemic amyloidosis at age 66, but his SEPTIN9 genotype could not be determined because genetic testing was not performed. This pedigree demonstrates marked intrafamilial variable expressivity. Discussion This report delineates the broad clinical spectrum associated with the SEPTIN9 R106W mutation in a Chinese pedigree, spanning from childhood to adulthood. Infection and childbirth were identified precipitating factors. The pronounced phenotypic variability underscores the necessity of early molecular diagnosis and cascade screening. Furthermore, prompt multidisciplinary management combining immunomodulation and structured rehabilitation achieved substantial functional recovery in the pediatric patient, highlighting the critical role of active inter vention in childhood-onset HNA.