The AP5B1 p.(Leu785Pro) variant is a frequent cause of late-onset macular dystrophy with variable extraocular manifestations.

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.

INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report.

KCNQ2 p.(Arg214Trp): systematic review with retrospective analysis and expanding the phenotype

Heterozygous pathogenic variants in the KCNQ2 gene underlie a broad phenotypic spectrum ranging from self-limited (familial) neonatal epilepsy (SeLNE) to developmental and epileptic encephalopathy or isolated intellectual disability. The KCNQ2 gene encodes subunits of a voltage-gated potassium channel involved in neuronal excitability, and its mutations are known to have both loss-of-function (LoF) and gain-of-function (GoF) effects, resulting in distinct neurological syndromes. The recurrent missense LoF variant KCNQ2 p.(Arg214Trp) has been previously reported in a single family with a presumed SeLNE phenotype, without detailed adult follow-up and with additional database-reported evidence suggesting a broader phenotype associated with this recurrent variant. Here, we report a family with two adult carriers of the heterozygous KCNQ2 p.(Arg214Trp) variant identified through whole-exome sequencing, including long-term follow-up into late adulthood. In addition, a literature review of previously reported cases carrying the same recurrent variant was performed. Both individuals presented with early-onset focal epilepsy with a relapsing course, characterized by prolonged seizure-free periods followed by recurrence in adulthood. The proband demonstrated transient motor regression, developmental delay, moderate intellectual disability, ataxia and fine motor impairment. The father exhibited milder cognitive impairment and additional comorbidities in later life. These findings challenge the concept of KCNQ2 p.(Arg214Trp) as a self-limited epilepsy-associated variant and indicate a broader phenotypic spectrum, with persistence of epilepsy and associated neurological and non-neurological comorbidities into adulthood. Our report provides new insights into adult outcomes, aiding in genetic counseling and the long-term management of affected individuals. More extensive studies with larger cohorts carrying this variant are necessary to better define the full phenotypic spectrum and to distinguish comorbidities associated with different etiological factors, including perinatal factors.

BHLHE22 monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, abnormal muscle tone and movement abnormalities.

The data establish BHLHE22 as a previously unrecognized neurodevelopmental disease gene that results in a distinct syndrome characterised by abnormalities in brain development, cognition, tone and movement.

A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization

The molecular and functional spectrum of SLC25A4-associated disease is expanded and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.

A de novoNR2F1 c.330 C > A variant in Bosch-Boonstra-Schaaf optic atrophy syndrome presenting with early-onset developmental and epileptic encephalopathy

The novel NR2F1 variant was classified as likely pathogenic according to ACMG guidelines, confirming the diagnosis of BBSOAS and the ARF3 variant, identified as a secondary finding of uncertain clinical significance, is unlikely to account for the patient's phenotype.