Loss of function variants in L2HGDH gene causing l -2-hydroxyglutaric aciduria

Background l -2-Hydroxyglutaric aciduria (L2HGA) is a rare progressive neurometabolic disorder with variable clinical presentation including cerebellar ataxia, psychomotor retardation, seizures, macrocephaly and speech problems. In this study, we aimed at identifying the genetic cause in two unrelated families suspected with L2HGA. Methods Exome sequencing was performed on two patients from family 1 with suspected L2HGA. MLPA analysis was carried out on the index patient of family 2 to detect deletions/duplications in the L2HGDH gene. Sanger sequencing was carried out to validate the identified variants and to confirm segregation of the variants in the family members. Results In family 1, a novel homozygous variant c.1156C > T resulting in a nonsense mutation p.Gln386Ter was identified in the L2HGDH gene. The variant segregated with autosomal recessive inheritance in the family. In family 2, a homozygous deletion of exon 10 in the L2HGDH gene was identified in the index patient using MLPA analysis. PCR validation confirmed the presence of the deletion variant in the patient which is not present in the unaffected mother or an unrelated control. Conclusion This study identified novel pathogenic variants in the L2HGDH gene in patients with L2HGA. These findings contribute to the understanding of the genetic basis of L2HGA and highlight the importance of genetic testing for diagnosis and genetic counseling of affected families.