PMID- 35873758
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220726
IS  - 1664-2295 (Print)
IS  - 1664-2295 (Electronic)
IS  - 1664-2295 (Linking)
VI  - 13
DP  - 2022
TI  - Identification of a Novel Nonsense Mutation in PLA2G6 and Prenatal Diagnosis in a 
      Chinese Family With Infantile Neuroaxonal Dystrophy.
PG  - 904027
LID - 10.3389/fneur.2022.904027 [doi]
LID - 904027
AB  - 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.
CI  - Copyright (c) 2022 Zou, Luo, Yuan, Xie, Yang, Huang, Yang and Liu.
FAU - Zou, Yongyi
AU  - Zou Y
AD  - Department of Medical Genetics, Jiangxi Maternal and Child Health Hospital, 
      Nanchang, China.
FAU - Luo, Haiyan
AU  - Luo H
AD  - Department of Medical Genetics, Jiangxi Maternal and Child Health Hospital, 
      Nanchang, China.
FAU - Yuan, Huizhen
AU  - Yuan H
AD  - Department of Medical Genetics, Jiangxi Maternal and Child Health Hospital, 
      Nanchang, China.
FAU - Xie, Kang
AU  - Xie K
AD  - Department of Medical Genetics, Jiangxi Maternal and Child Health Hospital, 
      Nanchang, China.
FAU - Yang, Yan
AU  - Yang Y
AD  - Department of Medical Genetics, Jiangxi Maternal and Child Health Hospital, 
      Nanchang, China.
FAU - Huang, Shuhui
AU  - Huang S
AD  - Department of Medical Genetics, Jiangxi Maternal and Child Health Hospital, 
      Nanchang, China.
FAU - Yang, Bicheng
AU  - Yang B
AD  - Department of Medical Genetics, Jiangxi Maternal and Child Health Hospital, 
      Nanchang, China.
FAU - Liu, Yanqiu
AU  - Liu Y
AD  - Department of Medical Genetics, Jiangxi Maternal and Child Health Hospital, 
      Nanchang, China.
LA  - eng
SI  - figshare/10.6084/m9.figshare.20188400.v1
PT  - Journal Article
DEP - 20220706
PL  - Switzerland
TA  - Front Neurol
JT  - Frontiers in neurology
JID - 101546899
PMC - PMC9298276
OTO - NOTNLM
OT  - PLA2G6
OT  - infantile neuroaxonal dystrophy
OT  - novel variant
OT  - prenatal diagnosis
OT  - whole exome sequencing
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/07/26 06:00
MHDA- 2022/07/26 06:01
PMCR- 2022/07/06
CRDT- 2022/07/25 03:41
PHST- 2022/03/25 00:00 [received]
PHST- 2022/05/09 00:00 [accepted]
PHST- 2022/07/25 03:41 [entrez]
PHST- 2022/07/26 06:00 [pubmed]
PHST- 2022/07/26 06:01 [medline]
PHST- 2022/07/06 00:00 [pmc-release]
AID - 10.3389/fneur.2022.904027 [doi]
PST - epublish
SO  - Front Neurol. 2022 Jul 6;13:904027. doi: 10.3389/fneur.2022.904027. eCollection 
      2022.