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

Neil V Morgan; Bryndis Yngvadottir; Mary O'Driscoll; Graeme R Clark; Diana Walsh; Ezequiel Martin; Louise Tee; Evan Reid; Hannah L Titheradge; Eamonn R Maher

doi:10.1093/braincomms/fcab002

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

Brain Commun. 2021 Jan 28;3(1):fcab002. doi: 10.1093/braincomms/fcab002. eCollection 2021.

Authors

Neil V Morgan¹, Bryndis Yngvadottir², Mary O'Driscoll³, Graeme R Clark², Diana Walsh⁴, Ezequiel Martin^{2

5}, Louise Tee⁶, Evan Reid^{2

7}, Hannah L Titheradge³, Eamonn R Maher²

Affiliations

¹ Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
² Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
³ West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's NHS Trust, Birmingham B15 2TG, UK.
⁴ West Midlands Regional Genetics Laboratory, Birmingham Women's and Children's NHS Trust, Birmingham B15 2TG, UK.
⁵ Oncology Department, Cancer Molecular Diagnostics Laboratory, University of Cambridge, Cambridge CB2 0XZ, UK.
⁶ Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
⁷ Cambridge Institute of Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.

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.