A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly.
Hum Mutat
; 39(6): 822-826, 2018 06.
Article
em En
| MEDLINE
| ID: mdl-29573052
ABSTRACT
Defective glycosylphosphatidylinositol (GPI)-anchor biogenesis can cause a spectrum of predominantly neurological problems. For eight genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7,833 parent-child trios and 1,792 singletons from the DDD study for biallelic variants in this gene-set uncovered a rare PIGH variant in a boy with epilepsy, microcephaly, and behavioral difficulties. Although only 2/2 reads harbored this c.1A > T transversion, the presence of â¼25 Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarly-affected sister was also homozygous. FACS analysis of PIGH-deficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPI-APs. Truncation of PIGH protein was consistent with the utilization of an in-frame start-site at codon 63. In summary, we describe siblings harboring a homozygous c.1A > T variant resulting in defective GPI-anchor biogenesis and highlight the importance of exploring low-coverage variants within autozygous regions.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Deficiências do Desenvolvimento
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Epilepsia
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Proteínas de Membrana
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Microcefalia
Tipo de estudo:
Risk_factors_studies
Limite:
Adolescent
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Animals
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido