COL4A1-related autosomal recessive encephalopathy in 2 Turkish children

COL4A1-related autosomal recessive encephalopathy in 2 Turkish children

Ahmet Yaramis, MD, Hanns Lochmuller, MD, Ana Topf, PhD, Ece Sonmezler, MSc, Elmasnur Yilmaz, MSc, Semra Hiz, MD, Uluc Yis, MD, Serdal Gungor, MD, Ayse Ipek Polat, MD, Pinar Edem, MD, Sergi Beltran, PhD, Steven Laurie, PhD, Aysenur Yaramis, BSc, Rita Horvath, MD, and Yavuz Oktay, PhD

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 neuro-genetic 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 hetero-zygous 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.