Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome

• Published in: Journal of human genetics Vol. 65; no. 10; pp. 911 - 915
• Main Authors: Brodsky, Nina N, Boyarchuk, Oksana, Kovalchuk, Tetyana, Hariyan, Tetyana, Rice, Andrew, Ji, Weizhen, Khokha, Mustafa, Lakhani, Saquib, Lucas, Carrie L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2020
• Subjects: Amino Acid Sequence; Angiomatosis; Angiomatosis - genetics; Brain Neoplasms - genetics; Cardiomegaly - genetics; Cardiomegaly - pathology; Child, Preschool; Fibrosis; Heterozygote; Humans; Intracellular Signaling Peptides and Proteins - genetics; Lung Diseases - genetics; Male; Models, Molecular; Neurodegeneration; Neurodegenerative Diseases - genetics; Pedigree; Point Mutation; Protein Conformation; Protein Domains; Sequence Alignment; Sequence Homology, Amino Acid; Syndrome; Thioredoxin; Whole Exome Sequencing
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-020-0776-0

Two variants in the ubiquitously expressed NHLRC2 gene have been reported to cause a lethal fibrotic cerebropulmonary disease termed fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome in three Finnish children. Our objective was to determine the genetic basis of disease in a new patient with clinical features of FINCA syndrome using whole-exome sequencing (WES) and confirmation by Sanger sequencing. The patient has one known and one novel variant in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P, respectively). p.H143P is extremely rare and is not present in the gnomAD database of >140,000 allele sequences from healthy humans. Both variants affect the highly conserved N-terminal thioredoxin (Trx)-like domain of NHLRC2 and are predicted to be damaging. We conclude that a compound heterozygous combination of a known and a novel variant in NHLRC2 causes FINCA syndrome in a 2-year-old Ukrainian patient, underscoring the importance of NHLRC2 as a central regulator of fibrosis.