Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia

Abstract

The glycine cleavage system H protein (GCSH) is an integral part of the glycine cleavage system with its additional involvement in the synthesis and transport of lipoic acid. We hypothesize that pathogenic variants in GCSH can cause variant nonketotic hyperglycinemia (NKH), a heterogeneous group of disorders with findings resembling a combination of severe NKH (elevated levels of glycine in plasma and CSF, progressive lethargy, seizures, severe hypotonia, no developmental progress, early death) and mitochondriopathies (lactic acidosis, leukoencephalopathy and Leigh‐like lesions on MRI). We herein report three individuals from two unrelated Indian families with clinical, biochemical, and radiological findings of variant NKH, harboring a biallelic start loss variant, c.1A > G in GCSH.

Pathogenic variants inGCSHencoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency

“…The p.Met1? translational initiation codon variant was found in two patients in this study and in three previously published patients ( 20 , 28 ), with a carrier incidence in gnomAD of 6.4 × 10 −5 . This variant resulted in greatly reduced, but not absent, H-protein, mostly of a lower MW in transfected COS7 cells.…”

“…)dup and the nonsense variant p.(Gln76 * ) are obvious loss-of-function changes and hence likely pathogenic. According to ACMG criteria, variant c.1A > G, previously reported in three consanguineous families ( 20 ), was considered a null variant due to loss of the normal translational initiation codon and is classified as pathogenic. The c.293-2_293–1insT variant on the paternal allele of patient 2 affects the 3′-acceptor splice site of exon 4.…”

“…Three consanguineous patients with the same variant in GCSH and without functional or structural analysis to prove pathogenicity ( 20 ) were previously reported. Here we report six new patients who presented with NKH and were found to carry bi-allelic variants in GCSH .…”

Genetic and phenotypic landscape of pediatric‐onset epilepsy in 142 Indian families: Counseling and therapeutic implications

“…Of these, 12 affected individuals from 10 unrelated families with findings of novel disease-gene associations have been published earlier and are provided in Table S3. [17][18][19][20][21][22][23][24][25][26] The current cohort consists of 149 individuals from 142 families with epilepsy and their demographics, clinical, and molecular details have been shown in Table 1. Of these, 88 (59%) are males and 61 (41%) are females.…”

“…We ascertained a total of 161 affected individuals from 152 unrelated families with epilepsy with or without any comorbidities. Of these, 12 affected individuals from 10 unrelated families with findings of novel disease‐gene associations have been published earlier and are provided in Table S3 17–26 …”