COL4A1 -related autosomal recessive encephalopathy in 2 Turkish children

Authors:
  • AYAhmet Yaramis
    Ahmet Yaramis
  • HLHanns Lochmüller
    Hanns Lochmüller
  • ATAna Töpf
    Ana Töpf
  • ESEce Sonmezler
    Ece Sonmezler
  • EYElmasnur Yilmaz
    Elmasnur Yilmaz
  • SHSemra Hiz
    Semra Hiz
  • UYUluc Yis
    Uluc Yis
  • SGSerdal Gungor
    Serdal Gungor
  • APAyse Ipek Polat
    Ayse Ipek Polat
  • PEPinar Edem
    Pinar Edem
  • SLSteven Laurie
    Steven Laurie
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Abstract
Objective This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases. Methods Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents. Results We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease. Conclusions COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1-related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.

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