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

Abstract

A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in GAD1 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 GAD1 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 HPDL gene was detected and found to segregate with disease status in both branches of the kindred. HPDL 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 HPDL were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that HPDL-related neurological disease may mimic spastic cerebral palsy and that GAD1 should not be included in diagnostic gene panels for inherited cerebral palsy.

Keywords: autosomal recessive; cerebral palsy; inherited.

Graphical Abstract

Figure 1

Family structure. A schematic representation of how two branches of the kindred were found to be connected (Branch A previously reported and Branch B subsequently ascertained, see text for details).

Figure 2

Mapping and sequence identification of a missense substitution in HPDL. (A) Genomewide SNP arrays performed in six affected individuals from family Branches A and B shows areas of extended homozygosity that are shared between all affected individuals and highlighted as red peaks on chromosome 1 (containing HPDL) and a smaller region on chromosome 10. (B) Initial whole-exome sequencing analysis in patient V: 5 revealed 41 candidate homozygous rare and novel sequence variants through filtering steps and only one of these variants mapped to the chromosome 1 candidate region (c.527T>C, p. Leu176Pro in HPDL). (C) Sanger sequencing traces showing the HPDL missense substitution. Upper panel shows mother of Branch A (IV: 2) in a heterozygous state (T/C) and lower panel the affected individual V: 1 in a homozygous state (C/C). (D) A comparison of sequence alignments of HPDL in 11 species showing the conservation of the p. Leu176 amino acid position where the variant p. Leu176Pro occurs.