case_images: PMC11786018_01
case_images: PMC11786018_02
case_images: PMC11786018_03
case_images: FIGLA variant identified in this study. (A) The gDNA and cDNA structures of FIGLA and the positions of the c.338A>G:p.(Tyr113Cys) found in this study and the 11 variants reported to date. Homozygous variants 1-3 are shown in red (c.338A>G:p.(Tyr113Cys) is surrounded with a rectangle), heterozygous variants 4-6 (which have been assessed as pathogenic or likely pathogenic) in blue, and heterozygous variants 7-12 (which have been evaluated as VUS) in black. The c.338A>G:p.(Tyr113Cys) variant resides on exon 2 encoding the bHLH domain spanning from ~65 to ~123 amino acids. (B) Electrochromatograms showing the c.338A>G substitution present in a homozygous condition in the two sisters and in a heterozygous condition in the parents (indicated with asterisks). The primers utilized are as follows: Forward, 5'-ctcagacaaggaggcagtgg-3'; and reverse, 5'-tcacttggcacagtgtctcg-3'. (C) Wild-type and variant FIGLA proteins predicted by AlphaFold2. The backbone common to Tyrosine and Cysteine is colored red, and the side chain unique to each amino acid is colored black.
case_images: RMB2-24-e12635-g001.jpg
case_images: PMC11786018_03_RMB2-24-e12635-g001.jpg
case_images: rmb212635-fig-0001
case_images: Consequently, we identified a novel homozygous FIGLA missense variant, NM_001004311.3:c.338A>G:p.(Tyr113Cys), in exon 2 encoding the bHLH domain in the two sisters (Figure 1A). This variant was confirmed by Sanger sequencing (Figure 1B). While PLINK analysis did not support consanguinity between the parents (Table S1), application of AutoMap and H3M2, which are utilized to find regions of homozygosity or runs of homozygosity (ROH) from WGS data, revealed that the two sisters had several ROH regions including a chromosome 2p13.3 segment involving FIGLA (Figure S1). Tyr113 residue and the variant protein with Cys113 residue using AlphaFold2 (https://alphafold.ebi.ac.uk/) (Figure 1C).