COL4A1 -related autosomal recessive encephalopathy in 2 Turkish children

Abstract

ObjectiveThis 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.MethodsWhole-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.ResultsWe 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.ConclusionsCOL4A1 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.

The RD‐Connect Genome‐Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases

“…Currently, the total number of affected participants is 13,676, of which 5,736 are discoverable through MME. The majority of submitted datasets have come from large European consortia projects, but in some cases, data from just a few sequenced individuals or trios from independent research groups have been uploaded and cases solved (e.g., Oktay et al, 2020; Owen et al, 2018; Permanyer et al, 2020; Topf et al, 2020; Yaramis et al, 2020). Before the initiation of the Solve‐RD project, the three largest projects which had used the system for primary analysis were NeurOmics (https://cordis.europa.eu/project/id/305121/reporting, n = 1,117 data sets), the Biobanking and Biomolecular Research Infrastructure—Large Prospective Cohorts (BBMRI‐LPC, https://cordis.europa.eu/project/id/313010/reporting) exome sequencing project ( n = 757), and the Consequitur project ( n = 626, Kurul et al, 2021).…”

“…Currently, the total number of affected participants is 13,676, of which 5,736 are discoverable through MME. The majority of submitted datasets have come from large European consortia projects, but in some cases, data from just a few sequenced individuals or trios from independent research groups have been uploaded and cases solved (e.g., Oktay et al, 2020;Owen et al, 2018;Permanyer et al, 2020;Topf et al, 2020;Yaramis et al, 2020). Before the initiation of the Solve-RD project, the three largest projects which had used the system for primary analysis were Kurul et al, 2021).…”

The NESHIE and CP Genetics Resource (NCGR): A database of genes and variants reported in neonatal encephalopathy with suspected hypoxic ischemic encephalopathy (NESHIE) and consequential cerebral palsy (CP)

“…COL4A1 provides the instruction for producing type IV collagen, an essential component of the vascular basement membrane. It is also among the top 0.62% of variation intolerant genes (RVIS score = −2.82) and has been associated with several notable phenotypes other than that of ischemia including vascular abnormalities, seizures and encephalopathy [ [111] , [112] , [113] , [114] ]. Thus, COL4A1 could provide a strong candidate for future studies investigating the existence of a genetic predisposition to NESHIE.…”

Genome-wide identification of Chiari malformation type I associated candidate genes and chromosomal variations

“…Type IV collagen family variations have been associated with various sporadic and genetic diseases. COL4A1 gene variations may cause poor speech development, cerebral palsy, epilepsy (Pasternak et al, 1980), porencephaly and adult stroke (Gould et al, 2006;van der Knaap et al, 2006), and encephalopathy (Yaramis et al, 2020). These diseases all suggest that COL4A1 mutations may cause impaired vasculature formation in the brain.…”