The c.529G>A (p.Ala177Thr) RNASEH2B Gene Pathogenic Variant as a First-Line Genetic Test for Aicardi-Goutières...

Aicardi-Goutières syndrome (AGS) is a hereditary encephalopathy characterized by marked clinical variability, mainly cerebral calcifications, cerebral atrophy, and leukodystrophy. The clinical diagnosis is difficult and can lead to high mortality. To date, nine genes are implicated, including RNASEH2A, RNASEH2B, RNASEH2C, TREX1, SAMHD1, ADAR1, IFIH1, LSM11, and RNU7-1. However, the p.A177T (c.529G>A) RNASEH2B gene mutation was described as the most recurrent mutation in several populations. Overall, there is a lack of research data on AGS in Morocco. Seven Moroccan patients from four families were referred for evaluation of Aicardi-Goutières syndrome (AGS). The first patient, a 1.5-year-old boy with leukodystrophy, underwent exome sequencing. The remaining six patients (a 2.5-year-old boy, three sisters aged 14, 10, and 2, and two sisters aged 5 and 3, along with another 2.5-year-old boy) were tested for the recurrent p.A177T (c.529G>A) RNASEH2B gene mutation using polymerase chain reaction and Sanger sequencing. Of the seven patients, five (two unrelated and three siblings) were homozygous for this pathogenic variant. Symptoms ranged from isolated spasticity with brain calcification to typical encephalopathy, with an average onset age of 1.5 years. Clinical variability was observed within one family. These findings demonstrate the phenotypic diversity of AGS and indicate that the first step of the diagnostic strategy should be genetic testing for the p.A177T (c.529G>A) RNASEH2B recurrent mutation.