PMC9452731_01
Pedigree of a three-generation family suffering from spinocerebellar ataxia. Males are represented by squares and females by circles. Intellectual disability is indicated by a black square, dystaxia by parallel horizontal lines, and microcephaly by parallel vertical lines. The black arrows indicated the probands (III1) mut+, mutation present; wt, wild type, het, heterozygous; hem, hemizygous.
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F1
The proband (III1) was an 8-year-old male who was referred to our medical genetic center by the neuropediatrician for microcephaly, intellectual disability, ataxia, gait disorder, and inability to speak (Figure 1). Pedigree analysis revealed that the proband's mother (II4) and grandmother (I3) were similarly affected with mild intellectual disability (Figure 1). S3). Among these variants, a novel c.1882G>C variant in the CASK gene (NM_003688.3), which results in an Asp-to-His amino acid change at codon 628 (p.D628H), is the most likely candidate variant for the MICPCH phenotype in this family. Subsequent Sanger sequencing confirmed that two affected males (III1, III2) were hemizygous and two females (I3, II4) with mild symptoms were heterozygous, whereas all unaffected family members were wild-type (I2, II2, III3) (Supplementary Figure S1).
Facial features and involuntary flexion of fingers (III1 and III2).
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F2
He had microcephaly, oval faces, and large ears (Figures 2A,B). He had motor coordination issues, fine and gross motor delays, and impaired hand function (involuntary flexion of the hands, Figures 2C,D). Consortium database, and our in-house database of 100 healthy Chinese adults. Comparative amino acid sequence alignment of CASK across various species showed the aspartic acid at codon 628 was highly conserved (Supplementary Figure S2).
Magnetic resonance images show severe hypoplasia of the cerebellum (III1 and III2).
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F3
Brain magnetic resonance imaging (MRI) revealed hypoplasia in both cerebellar hemispheres and the vermis in these siblings (III1 and III2) (Figure 3). Brain MRI of their parents (II3 and II4) exhibited unaffected cerebellar structures (Figures 3G-I).
Structural prediction and position mapping of D628H of CASK protein. (A) Structural prediction of wild-type D and the mutant H residues at the 628  position. Bold, the wild-type and mutant side chain are shown in blue and red, respectively. (B) Position mapping of previously reported missense mutations p.D628Hin this study, CASK protein.
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F4
By entering protein sequences into the SWISS-MODEL website (https://swissmodel.expasy.org) and then visualizing with RasMol (http://www.rasmol.org), structural models of the wild-type and mutant CASK proteins were created (Figure 4). However, the predicted Arg-Asp salt bridge will be broken by replacing the negatively charged aspartic acid with the non-polar amino acid histidine, potentially disrupting the domain and the interaction between CASK and neurexin (Figure 4).