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

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Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL. / Morgan, Neil; Yngvadottir, Bryndis; O'Driscoll, Mary; Clark, Graeme R.; Walsh, Diana; Martin, Ezequiel; Tee, Louise; Reid, Evan; Titheradge, Hannah; Maher, Eamonn.

In: Brain Communications, Vol. 3, No. 1, fcab002, 16.01.2021.

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Morgan, Neil ; Yngvadottir, Bryndis ; O'Driscoll, Mary ; Clark, Graeme R. ; Walsh, Diana ; Martin, Ezequiel ; Tee, Louise ; Reid, Evan ; Titheradge, Hannah ; Maher, Eamonn. / Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL. In: Brain Communications. 2021 ; Vol. 3, No. 1.

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@article{cadf2c3af68547299600142314c40110,
title = "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",
author = "Neil Morgan and Bryndis Yngvadottir and Mary O'Driscoll and Clark, {Graeme R.} and Diana Walsh and Ezequiel Martin and Louise Tee and Evan Reid and Hannah Titheradge and Eamonn Maher",
year = "2021",
month = jan,
day = "16",
doi = "10.1093/braincomms/fcab002",
language = "English",
volume = "3",
journal = "Brain Communications",
issn = "2632-1297",
publisher = "Oxford University Press",
number = "1",

}

RIS

TY - JOUR

T1 - Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL

AU - Morgan, Neil

AU - Yngvadottir, Bryndis

AU - O'Driscoll, Mary

AU - Clark, Graeme R.

AU - Walsh, Diana

AU - Martin, Ezequiel

AU - Tee, Louise

AU - Reid, Evan

AU - Titheradge, Hannah

AU - Maher, Eamonn

PY - 2021/1/16

Y1 - 2021/1/16

N2 - 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.

AB - 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.

KW - autosomal recessive

KW - cerebral palsy

KW - inherited

U2 - 10.1093/braincomms/fcab002

DO - 10.1093/braincomms/fcab002

M3 - Article

VL - 3

JO - Brain Communications

JF - Brain Communications

SN - 2632-1297

IS - 1

M1 - fcab002

ER -