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A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly.

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 ?25 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.

SUBMITTER: Pagnamenta AT 

PROVIDER: S-EPMC6001798 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly.

Pagnamenta Alistair T AT   Murakami Yoshiko Y   Anzilotti Consuelo C   Titheradge Hannah H   Oates Adam J AJ   Morton Jenny J   Kinoshita Taroh T   Kini Usha U   Taylor Jenny C JC  

Human mutation 20180330 6

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 transversi  ...[more]

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