Phenotypic and genotypic expansion of TRAPPC12-related disorder

Objectives: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity (PEBAS)(MIM#617669) is a recently described rare genetic disorder caused due to biallelic variants in TRAPPC12. The phenotypic features range from fetal hydrocephalus to childhood-onset progressive encephalopathy. Till date, twelve individuals from eight families have been reported. Methods: We ascertained five individuals from three unrelated consanguineous families: an affected female (P1) from family 1, two affected siblings (P2 and P3) from family 2 and two affected siblings (P4 and P5) from family 3. We performed singleton exome sequencing for P1, P2 and P4 followed by validation and segregation by Sanger sequencing. Reverse-transcriptase PCR was carried out in P1 to validate the predicted splicing aberration. Results: We report five individuals from three Indian families harboring novel homozygous variants: one splicing variant, c.1776+16C>A (family 1) and two missense variants, c.1604C>T (family 2) and c.1892T>G (family 3) in TRAPPC12. The splicing variant c.1776+16C>A results in frameshift and produces a truncated transcript observed both in peripheral blood as well as in patient fibroblasts. The clinical and neuroimaging findings in family 1 and 3 were comparable to previously reported individuals. P1 and P2 had elevated creatinine phosphokinase level indicating muscle involvement, not reported previously. Also, the clinical findings in individuals of family 2 were novel. P2 presented with mild global delay followed by progressive motor regression after 7 years and hypertrophic cardiomyopathy. P3 presented with isolated intellectual disability. Conclusion: Our report expands the genotype and phenotype of TRAPPC12-related disorder.