A novel de novo CACNA1G variant p.(Arg1553Gln) associated with neurodevelopmental delay and cerebellar hypoplasia: Expanding the phenotypic spectrum

Selek A., Orpay F., ÜNAY B.

European Journal of Medical Genetics, cilt.82, 2026 (SCI-Expanded, Scopus)

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 82
  • Basım Tarihi: 2026
  • Doi Numarası: 10.1016/j.ejmg.2026.105088
  • Dergi Adı: European Journal of Medical Genetics
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO)
  • Anahtar Kelimeler: CACNA1G, Cav3.1, Neurodevelopmental disorder, Cerebellar hypoplasia, de-novo variant
  • Sağlık Bilimleri Üniversitesi Adresli: Hayır

Özet

CACNA1G encodes the Cav3.1 T-type calcium channel, a key regulator of neuronal excitability and thalamocortical rhythmicity. Pathogenic variants have been associated with neurodevelopmental disorders, frequently accompanied by epilepsy and cerebellar abnormalities. We report a patient with global developmental delay and autism spectrum disorder who developed progressive gait instability and was found to harbor a novel de-novo CACNA1G variant, c.4658G ' A p.(Arg1553Gln). Notably, the patient had no history of seizures and normal electroencephalographic findings. Brain magnetic resonance imaging revealed cerebellar and vermian hypoplasia, consistent with previously described cases, as well as an incidental intracranial lipoma. Distinctive clinical features included macrocephaly and appendicular hypertonia, findings not previously reported in association with CACNA1G-related disorders and potentially expanding the phenotypic spectrum. The identified variant is located in the intracellular III–IV linker region of Cav3.1, outside the canonical pore-forming domains where most epilepsy-associated variants cluster. Its absence from the literature and public variant databases supports its novelty. This case broadens the clinical and molecular spectrum of CACNA1G-related disease and highlights phenotypic variability, particularly in patients without epilepsy.