A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly

Abstract

The calcium/calmodulin-dependent serine protein kinase gene (CASK) mutations are associated with various neurological disorders; a syndrome of intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH), FG syndrome, X-linked ID with/without nystagmus, epileptic encephalopathy, and autistic spectrum disorder (ASD). Next generation sequencing was performed to elucidate genetic causes in siblings exhibiting developmental disorders, and a novel CASK mutation, c.1424G>T (p.Ser475Ile), was detected in a male patient with ID, ASD, and microcephaly. Radiological examination of his brain showed no structural abnormality. The identified mutation was shared with the healthy mother and a younger sister exhibiting ASD. Although the mother showed a skewed X-chromosome inactivation (XCI) pattern, the sister showed a paradoxical XCI pattern. This would explain why this sister possessed a normal intellectual level, but showed the same ASD symptoms as the affected brother. A novel CASK mutation was identified in two siblings with ID and/or ASD, suggesting a relationship between the CASK mutation and ASD. Recently performed large molecular cohorts for patients with developmental disorders suggest that CASK is one of the genes related to developmental disorders. For better understanding of genotype-phenotype correlation in ASD cases with CASK mutations, more information should be accumulated.

Keywords: Autism; X-chromosome inactivation; manifesting carrier; next generation sequencing; obligate carrier.

Figure 1.

Results of brain magnetic resonance imaging. There is no abnormality, including the volume of cerebellum. T2-sagittal (A) and T1-axial images (B) examined at 5 years of age.

Figure 2.

Results of genetic studies. (A) Filtering steps and the number of filtered variants are shown in inverted pyramids. The Human Genetic Variation Database (HGVD) (http://www.genome.med.kyoto-u.ac.jp/SnpDB) provided from Kyoto University was used for the filtering. (B) The Integrative Genomics Viewer (IGV) shows the identified CASK variant in 100% of reads. (C) Electropherograms of Sanger sequencing. The father shows the wild type sequence, whereas the mother and patient 2 exhibit heterozygous status. Patient 1 is completely hemizygous for the mutation. (D) The neighboring amino-acid sequences are compared among species. The affected codon “S” is conserved among species.

Figure 3.

Results of X-chromosome inactivation (XCI) patterns. The mother shows a skewed XCI pattern, because one of the X-chromosomes (not shared with patient 2) is almost completely missing after digestion by a methylation sensitive restriction enzyme. Patient 2 shows a paradoxical pattern with predominant XCI in the paternally derived allele.