Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in <i>HPDL</i>

Abstract

A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in <i>GAD1</i> was described as a candidate mutation in a single family diagnosed with autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513). Following the ascertainment of a further branch of the CPSQ1 kindred, we found that the previously reported <i>GAD1</i> variant did not segregate with the neurological disease phenotype in the recently ascertained branch of the kindred. Following genetic linkage studies to map autozygous regions and whole-exome sequencing, a missense variant (c.527 T > C; p. Leu176Pro, rs773333490) in the <i>HPDL</i> gene was detected and found to segregate with disease status in both branches of the kindred. <i>HPDL</i> encodes a 371-amino acid protein (4-Hydroxyphenylpyruvate Dioxygenase Like) that localizes to mitochondria but whose function is uncertain. Recently, biallelic loss of function variants and missense substitution-causing variants in <i>HPDL</i> were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that <i>HPDL-</i>related neurological disease may mimic spastic cerebral palsy and that <i>GAD1</i> should not be included in diagnostic gene panels for inherited cerebral palsy.