Identification of a de novo variant in BCAP31 by full genome analysis
Since exome sequencing did not reveal candidate variants in the primary screen, we performed Chromium (10x Genomics) Linked‐Reads whole genome sequencing on the patient and her biological parents. All variants were called and phased with Long Ranger BASIC and ALIGN Pipelines and followed by filters of allelic frequency with threshold set at 0.01 for missense, indels and splice site mutations. Then, the remaining variants after filtering were evaluated according to three possible genetic models: autosomal recessive, autosomal dominant and X-linked recessive. As the parents were without the disorder, only de novo variants were considered in the autosomal dominant and X-linked recessive models. After determining that the sequence quality was high by expert inspection, and literature review that showed good correlation with the associated clinical phenotype, we identified a de novoheterozygous variant in the BCAP31 gene as a prime candidate for the patient’s condition. This mutation is confirmed by Sanger DNA sequencing and is found on the plus strand of hg38 chrX:153723153C>T that predicts to cause NM_001256447.2:c.92G>A, p.Arg31Lys change (Fig. 2). This novel variant has not been reported in Taiwan BioBank or any other database. Even with careful analysis of the sequencing and optical mapping data, no other disease-causing variant (including SNVs, small indels, and structural variation) could be identified in the patient’sBCAP31 gene.