Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry.CYP4F22基因突变可导致常染色体隐性遗传性先天性鱼鳞病（autosomal recessive congenital ichthyosis, ARCI），但目前仅不到10%的ARCI患者携带CYP4F22突变。本研究针对92名西班牙受试者组成的队列，旨在明确其ARCI患者的分子发病机制，采用直接桑格测序（Sanger sequencing）结合多基因靶向下一代测序（next-generation sequencing, NGS）面板开展突变分析。研究从中筛选出8个ARCI家系（其中3个具有摩洛哥血统），共携带5种不同的CYP4F22突变，其中2种为新发突变。生物信息学分析显示，上述突变均位于该蛋白高度保守的氨基酸残基位点，可能对其结构与功能产生影响。8个家系中有7个均携带高频出现的CYP4F22变异c.1303C>T; p.(His435Tyr)。研究人员对该c.1303C>T变异携带者进行了10个位于CYP4F22基因侧翼的微卫星标记（microsatellite marker）基因分型，重构出长度为12Mb的单倍型（haplotype）。西班牙携带者群体中存在一段长度2.52Mb的优势单倍型，提示其拥有最近的共同祖先。西班牙与摩洛哥家系共享一段长度为1.2Mb的核心单倍型。本研究采用多种方法估算了西班牙籍携带者群体的最近共同祖先时间（time to the most recent common ancestor, TMRCA），通过DMLE与BDMC2两款算法计算该变异的起源时间，结果显示c.1303C>T变异大约起源于2925至4925年前，而西班牙携带者家系的共同祖先则生活于13世纪。本研究共报道了5种CYP4F22突变（其中2种为新发），丰富了当前已收录的CYP4F22突变谱。此外，本研究结果提示高频变异c.1303C>T在西班牙人群中存在奠基者效应（founder effect），且该变异的携带者家系均起源于一位可能具有非洲血统的共同祖先。