Yield of Whole Exome Sequencing in Children With Cryptogenic Cerebral Palsy

Recent studies indicate that a significant number of patients with cerebral palsy (CP) may have a genetic cause. However, data from India are limited, where inheritance patterns are likely to be different. We examined the yield of next-generation sequencing in identifying the genetic causes of CP in children with unclear etiology and described the genetic spectrum found.

Whole-exome sequencing (WES) was performed on 71 children with CP (aged under 18 years, with a stable, nonprogressive course) in whom no acquired cause was identified clinically or radiologically.

The yield of WES was 53.52% (38 of 71 cases) for pathogenic (P) and likely-pathogenic (LP) variants, and 78.87% when including variants of uncertain significance. We identified 54 variants (12 P, 24 LP, and 18 variants of uncertain significance) across 46 genes, along with two pathogenic copy number variants in 38 of the 71 cases. Genes such as AP4M1, ACSF1, AP4S1, and HACE1 showed P/LP variants in more than 1 case. The most common inheritance pattern (found in 30 of 38 cases) was autosomal recessive (78.95%), mainly due to high consanguinity in the cohort [53 of 71 (74.65%)]. We identified nine hereditary spastic paraplegia genes in 13 patients, three cases with Aicardi-Goutières syndrome genes, and four with genes associated with congenital disorders of glycosylation. The genes exhibited diverse pathogenic mechanisms, reflecting the heterogeneity of CP genes.

Careful selection of cohorts can enhance the genetic yield of WES in CP. Autosomal recessive variants are more common in populations with high rates of consanguinity.