The PHF6 Mutation c.1A>G; pM1V Causes Börjeson-Forsman-Lehmann Syndrome in a Family with Four Affected Young Boys.

The family presented with 4 boys, 2 sets of brothers, with unexplained intellectual disability. Numerous analyses had been conducted over more than a decade, without reaching a final clinical or molecular diagnosis. According to the pedigree, an X-linked inheritance pattern was strongly suspected. Whole-exome sequencing (WES) with targeted analysis of the coding regions of the X chromosome was carried out in the 4 boys, their mothers, and their shared grandmother. A filtering process searching for nonsynonymous variants and variants in the exon-intron boundaries revealed one variant, c.1A>G; pM1V, in the first codon of the PHF6 gene. The variant was hemizygous in the 4 boys and heterozygous in the 2 mothers and the grandmother. Mutations in the PHF6 gene are known to cause Börjeson-Forsman-Lehmann syndrome (BFLS). The boys were reexamined after the finding of the mutation, and the phenotype fitted perfectly with BFLS. The mutation found in the PHF6 gene is causative for the intellectual disability in this family. We also conclude that WES of the X chromosome is a powerful tool in families where an X-linked inheritance pattern is suspected.