The first case of Al-Raqad syndrome in Japan is associated with a homozygous DCPS exonic variant resulting in aberrant splicing.

BACKGROUND

Cases of unexplained neurodevelopmental disorder (NDD) are often accompanied by multiple congenital anomalies. With recent advances in genetic analysis technology, whole-exome sequencing (WES) has become a powerful diagnostic tool for unexplained NDD patients, but variants of unknown significance are sometimes detected in them.

METHODS

WES identified a variant in a 2-year-old boy with NDD associated with multiple congenital anomalies who had no abnormal findings in G-banding and array comparative genomic hybridization (array CGH). mRNA analysis was performed on the variant using the patient's peripheral blood leukocytes following in silico analysis to confirm its effect on splicing.

RESULTS

WES revealed a novel homozygous single base substituting variant of unknown significance (VUS), which was carried heterozygously by the patient's parents (DCPS, NM_014026.6: c.200A>G, p.(Lys67Arg)). In silico analysis predicted that this variant may cause aberrant splicing, and mRNA analysis revealed a 48-bp deletion from the 3' end of exon 1. Biallelic variants of DCPS are known to cause Al-Raqad syndrome, a quite rare disorder which presents NDD with multiple malformations. This disease has been reported in only eight individuals from five Middle Eastern or Caucasian families but never in the Japanese but the symptoms of the present case were similar to reported cases of this syndrome.

DISCUSSION: We successfully diagnosed a case of unexplained NDD as Al-Raqad syndrome by WES along with mRNA analysis. Single base substitution with judged VUS can be pathogenic by causing aberrant splicing and, therefore, in silico analysis and subsequent RNA sequence are necessary to prove its pathogenicity.