Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family

Abstract

Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.

Generalized Dystonia as a Cardinal Manifestation of Combined Oxidative Phosphorylation Deficiency 1

“…Another reason could be interaction with other mitochondrial proteins and ethnic diversity. 10 To our knowledge, this is the first case of GFM1 mutation whose disease onset was beyond the first decade of life, with generalized dystonia as a predominant manifestation. To conclude, GFM1-linked diseases are phenotypically and genotypically heterogeneous.…”

“…9 Our patient had a predominant neurological involvement in the form of generalized dystonia with a stable clinical course over more than a decade. Long-term survival is rare, with a maximum reported follow-up of 5.5-17 years 3,9,10 (Table S2). The mechanism behind this is not entirely clear but may be related to the location of the mutation, as suggested by Galmiche et al 4 Mutations located in the central part of mtEFG1 protein were associated with hepatic failure, while those associated with neurological involvement were located in the peripheral part.…”

Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families

“…The alignment covered approximately 99.3% of the RefSeq protein coding region. Variant calling and filtration were performed using standard data analysis pipelines of 3Billion Inc., South Korea, as described elsewhere 20–22 . Variants with a co‐allele frequency of > 5% were filtered out according to the American College of Medical Genetics (ACMG) guidelines 23 .…”

“…Variant calling and filtration were performed using standard data analysis pipelines of 3Billion Inc., South Korea, as described elsewhere. [20][21][22] Variants with a co-allele frequency of > 5% were filtered out according to the American College of Medical Genetics (ACMG) guidelines. 23 The frequency of the variant in the general population was checked using ensembl.org/index.html) and the 1000 Genomes browser (https:// www.internationalgenome.org/1000-genomes-browsers/index.html).…”

Feasibility of measuring eye–hand coordination in children with developmental delay using Sanet Vision Integrator

“…The term “developmental delay” describes a broad phenotype when a child is unable to meet the developmental milestones when compared with their peers from the same demographics (Centers for Disease Control and Prevention, 2022; Choo et al, 2019). The etiology of developmental delay can be idiopathic, genetic, environmental, or psychosocial, and it can result in impairment in one or more domains of gross and fine motor development, speech and language skills, cognitive performance, and so on (Abo El Elella et al, 2017; Choo et al, 2019; Khan & Leventhal, 2022). Such a developmental delay can impact the daily living skills and activities of the child.…”