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Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a Chinese Family With Infantile Neuroaxonal Dystrophy

BACKGROUND AND PURPOSE: Infantile neuroaxonal dystrophy (INAD) is a subtype of PLA2G6-Associated Neurodegeneration (PLAN) with an age of early onset and severe clinical phenotypes of neurodegeneration. Individuals affected with INAD are characterized by rapid progressive psychomotor deterioration, n...

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Autores principales: Zou, Yongyi, Luo, Haiyan, Yuan, Huizhen, Xie, Kang, Yang, Yan, Huang, Shuhui, Yang, Bicheng, Liu, Yanqiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298276/
https://www.ncbi.nlm.nih.gov/pubmed/35873758
http://dx.doi.org/10.3389/fneur.2022.904027
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author Zou, Yongyi
Luo, Haiyan
Yuan, Huizhen
Xie, Kang
Yang, Yan
Huang, Shuhui
Yang, Bicheng
Liu, Yanqiu
author_facet Zou, Yongyi
Luo, Haiyan
Yuan, Huizhen
Xie, Kang
Yang, Yan
Huang, Shuhui
Yang, Bicheng
Liu, Yanqiu
author_sort Zou, Yongyi
collection PubMed
description BACKGROUND AND PURPOSE: Infantile neuroaxonal dystrophy (INAD) is a subtype of PLA2G6-Associated Neurodegeneration (PLAN) with an age of early onset and severe clinical phenotypes of neurodegeneration. Individuals affected with INAD are characterized by rapid progressive psychomotor deterioration, neuroregression, and hypotonia followed by generalized spasticity, optic atrophy, and dementia. In this case, we aimed to identify the underlying causative genetic factors of a Chinese family with two siblings who presented with walking difficulty and inability to speak. We provided a prenatal diagnosis for the family and information for the prevention of this genetic disease. METHODS: Retrospective clinical information and magnetic resonance imaging (MRI) findings of the proband were collected. Trio-whole exome sequencing (WES) including the proband and his parents was performed to explore the genetic causes, while Sanger sequencing was subsequently used to validate the variants identified by Trio-WES in the pedigree. Furthermore, prenatal molecular genetic diagnosis was carried out through amniocentesis to investigate the status of pathogenic mutations in the fetus by Sanger sequencing at an appropriate gestational age. RESULTS: The two siblings were both clinically diagnosed with rapid regression in psychomotor development milestones. Brain MRI showed cerebellar atrophy and typical bilaterally symmetrical T2/FLAIR hyperintense signal changes in periventricular areas, indicating periventricular leukomalacia, and myelin sheath dysplasia. Trio-WES revealed two heterozygous variants in PlA2G6 associated with clinical manifestations in the proband: a novel maternally inherited variant c.217C>T (p.Gln73(*)) and a previously reported paternally inherited recurrent pathogenic variant c.1894C>T (p.Arg632Trp). These two heterozygous mutations were also detected in the younger brother who had similar clinical features as the proband. The novel variant c.217C>T was classified as “pathogenic (PVS1 + PM2 + PP3),” while the variant c.1894C>T was “pathogenic” (PS1 + PM1 + PM2 + PM3 + PP3) based on the latest American College of Medical Genetics and Genomics (ACMG) guidelines on sequence variants. Combining the molecular evidence and clinical phenotypes, the diagnosis of INAD was established for the two affected siblings. The two variants that were identified were considered the causative mutations for INAD in this family. Prenatal diagnosis suggested compound heterozygous mutations of c.217C>T and c.1894C>T in the fetus, indicating a high risk of INAD, and the parents chose to terminate the pregnancy. CONCLUSION: We identified a novel pathogenic mutation that broadens the mutation spectrum of PLA2G6 and will provide clues for the molecular diagnosis of INAD. Furthermore, our study has helped to elucidate the causative genetic factors of this Chinese family with INAD effectively and efficiently by using the emerging Trio-WES strategy and providing precise genetic counseling for this family.
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spelling pubmed-92982762022-07-21 Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a Chinese Family With Infantile Neuroaxonal Dystrophy Zou, Yongyi Luo, Haiyan Yuan, Huizhen Xie, Kang Yang, Yan Huang, Shuhui Yang, Bicheng Liu, Yanqiu Front Neurol Neurology BACKGROUND AND PURPOSE: Infantile neuroaxonal dystrophy (INAD) is a subtype of PLA2G6-Associated Neurodegeneration (PLAN) with an age of early onset and severe clinical phenotypes of neurodegeneration. Individuals affected with INAD are characterized by rapid progressive psychomotor deterioration, neuroregression, and hypotonia followed by generalized spasticity, optic atrophy, and dementia. In this case, we aimed to identify the underlying causative genetic factors of a Chinese family with two siblings who presented with walking difficulty and inability to speak. We provided a prenatal diagnosis for the family and information for the prevention of this genetic disease. METHODS: Retrospective clinical information and magnetic resonance imaging (MRI) findings of the proband were collected. Trio-whole exome sequencing (WES) including the proband and his parents was performed to explore the genetic causes, while Sanger sequencing was subsequently used to validate the variants identified by Trio-WES in the pedigree. Furthermore, prenatal molecular genetic diagnosis was carried out through amniocentesis to investigate the status of pathogenic mutations in the fetus by Sanger sequencing at an appropriate gestational age. RESULTS: The two siblings were both clinically diagnosed with rapid regression in psychomotor development milestones. Brain MRI showed cerebellar atrophy and typical bilaterally symmetrical T2/FLAIR hyperintense signal changes in periventricular areas, indicating periventricular leukomalacia, and myelin sheath dysplasia. Trio-WES revealed two heterozygous variants in PlA2G6 associated with clinical manifestations in the proband: a novel maternally inherited variant c.217C>T (p.Gln73(*)) and a previously reported paternally inherited recurrent pathogenic variant c.1894C>T (p.Arg632Trp). These two heterozygous mutations were also detected in the younger brother who had similar clinical features as the proband. The novel variant c.217C>T was classified as “pathogenic (PVS1 + PM2 + PP3),” while the variant c.1894C>T was “pathogenic” (PS1 + PM1 + PM2 + PM3 + PP3) based on the latest American College of Medical Genetics and Genomics (ACMG) guidelines on sequence variants. Combining the molecular evidence and clinical phenotypes, the diagnosis of INAD was established for the two affected siblings. The two variants that were identified were considered the causative mutations for INAD in this family. Prenatal diagnosis suggested compound heterozygous mutations of c.217C>T and c.1894C>T in the fetus, indicating a high risk of INAD, and the parents chose to terminate the pregnancy. CONCLUSION: We identified a novel pathogenic mutation that broadens the mutation spectrum of PLA2G6 and will provide clues for the molecular diagnosis of INAD. Furthermore, our study has helped to elucidate the causative genetic factors of this Chinese family with INAD effectively and efficiently by using the emerging Trio-WES strategy and providing precise genetic counseling for this family. Frontiers Media S.A. 2022-07-06 /pmc/articles/PMC9298276/ /pubmed/35873758 http://dx.doi.org/10.3389/fneur.2022.904027 Text en Copyright © 2022 Zou, Luo, Yuan, Xie, Yang, Huang, Yang and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Zou, Yongyi
Luo, Haiyan
Yuan, Huizhen
Xie, Kang
Yang, Yan
Huang, Shuhui
Yang, Bicheng
Liu, Yanqiu
Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a Chinese Family With Infantile Neuroaxonal Dystrophy
title Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a Chinese Family With Infantile Neuroaxonal Dystrophy
title_full Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a Chinese Family With Infantile Neuroaxonal Dystrophy
title_fullStr Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a Chinese Family With Infantile Neuroaxonal Dystrophy
title_full_unstemmed Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a Chinese Family With Infantile Neuroaxonal Dystrophy
title_short Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a Chinese Family With Infantile Neuroaxonal Dystrophy
title_sort identification of a novel nonsense mutation in pla2g6 and prenatal diagnosis in a chinese family with infantile neuroaxonal dystrophy
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298276/
https://www.ncbi.nlm.nih.gov/pubmed/35873758
http://dx.doi.org/10.3389/fneur.2022.904027
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