CASK – Syndromic X-linked Intellectual Disability Najm Type

Pathogenic variants in the X-linked gene CASK (calcium/calmodulin-dependent serine protein kinase) cause a spectrum of neurodevelopmental disorders, most notably intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) and syndromic X-linked intellectual disability Najm type (MONDO:0010417). CASK is highly expressed in the developing brain, where it scaffolds synaptic proteins and regulates transcriptional complexes essential for neuronal differentiation.

CASK-related Najm type exhibits an X-linked dominant inheritance with predominantly de novo heterozygous variants in affected females and mosaic or hemizygous males. In a series of 14 patients, 13 harbored de novo intragenic loss-of-function mutations (PMID:22452838) and in a larger cohort of 41 MICPCH cases, CASK aberrations were detected in 32 individuals (PMID:28783747). Additional single-case reports further expand the genetic spectrum, including novel frameshift and splice variants.

Segregation analysis in a Chinese family demonstrated co-segregation of a novel missense variant c.1882G>C (p.Asp628His) with disease in two affected male siblings and two mildly affected female relatives, confirming familial transmission and variable expressivity (PMID:36092876). Overall, more than 45 unrelated probands with de novo truncating, splice-site, or missense variants have been reported.

The variant spectrum includes at least ten truncating and splice-site variants, as well as multiple missense changes affecting conserved domains. A recurrent missense variant c.638T>G (p.Leu213Arg) has been shown to reduce CASK protein stability and function in patient-derived cells (PMID:35668446).

Functional studies across cellular and animal models support a haploinsufficiency mechanism. Zebrafish CASK knockdown recapitulates microcephaly and hindbrain hypoplasia, while in vitro assays reveal disrupted interactions with neurexin, TBR1, and Liprin-α, impairing synaptic scaffold assembly and transcriptional regulation of NMDAR2b (PMID:29691940; PMID:36137748).

Together, the robust genetic and experimental concordance in CASK-related Najm type support a definitive gene–disease association. Clinical testing for CASK variants should be prioritized in patients with syndromic intellectual disability, microcephaly, and pontine-cerebellar hypoplasia. CASK variant identification enables accurate diagnosis, informs prognosis, and guides genetic counseling.

References

• Orphanet Journal of Rare Diseases • 2012 • Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient. PMID:22452838
• PloS One • 2017 • Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH). PMID:28783747
• Frontiers in Genetics • 2022 • Case Report: Identification of a novel CASK missense variant in a Chinese family with MICPCH. PMID:36092876
• BMC Medical Genomics • 2022 • A novel missense variant in the CASK gene causes intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia. PMID:35668446
• Human Mutation • 2018 • Novel CASK mutations in cases with syndromic microcephaly. PMID:29691940
• Life Science Alliance • 2022 • Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain. PMID:36137748

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