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A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder

Carolina I Galarreta1, Karen Wong2, Jason Carmichael1

  • 1Medical Genetics and Metabolism Department, Valley Children's Hospital, Madera, California, USA.

American Journal of Medical Genetics. Part A
|May 5, 2023
PubMed

Insights

Zellweger spectrum disorder (ZSD) is a rare genetic condition. A specific PEX6 gene variant, Gly470Ala, was identified in nine infants of Mixtec ancestry, suggesting a founder effect and highlighting the need for broader genetic screening.

Area of Science:

  • Genetics
  • Biochemistry
  • Pediatrics

Background:

  • Zellweger spectrum disorder (ZSD) comprises a group of severe autosomal recessive conditions.
  • These disorders stem from pathogenic variants in PEX genes crucial for peroxisomal biogenesis.
  • Peroxisomal dysfunction impacts multiple organ systems, leading to significant health challenges.

Purpose of the Study:

  • To describe a cohort of infants with severe neonatal ZSD features.
  • To investigate a specific PEX6 variant (c.1409G>C [p.Gly470Ala]) identified in this cohort.
  • To explore the potential founder effect of this variant in the Mixtec population.

Main Methods:

  • Clinical and biochemical evaluation of nine infants presenting with neonatal ZSD symptoms.
  • Genetic analysis to identify homozygous pathogenic variants, focusing on PEX6.
  • Newborn screening (NBS) data review, including C26:0-lysophosphatidylcholine levels and ABCD1 variant screening.

Main Results:

  • Nine infants, all of Mixtec ancestry, were homozygous for the PEX6 c.1409G>C (p.Gly470Ala) variant.
  • These infants presented with severe neonatal features consistent with ZSD and had elevated C26:0-lysophosphatidylcholine.
  • No reportable variants in ABCD1 were found in these infants, differentiating their presentation from X-linked adrenoleukodystrophy.

Conclusions:

  • The PEX6 Gly470Ala variant may be a founder mutation in the Mixtec population of Central California.
  • ZSD should be considered in neonates with severe hypotonia and enlarged fontanelles, particularly with abnormal NBS results, Mixtec ancestry, or a history of infant death.
  • Further research is needed to understand the natural history of ZSD associated with the Gly470Ala variant and to establish genotype-phenotype correlations.

Keywords:
MixtecPEX6Zellweger spectrum disorderfounder effect

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