A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy

Abstract

GEMIN5 is a multifunctional RNA-binding protein required for the assembly of survival motor neurons. Several bi-allelic truncating and missense variants in this gene are reported to cause a neurodevelopmental disorder characterized by cerebellar atrophy, intellectual disability (ID), and motor dysfunction. Whole exome sequencing of a Pakistani consanguineous family with three brothers affected by ID, cerebral atrophy, mobility, and speech impairment revealed a novel homozygous 3bp-deletion NM_015465.5:c.3162_3164del that leads to the loss of NM_015465.5 (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) amino acid in one of the α-helixes of the tetratricopeptide repeats of GEMIN5. In silico 3D representations of the GEMIN5 dimerization domain show that this variant likely affects the orientation of the downstream sidechains out of the helix axis, which would affect the packing with neighboring helices. The phenotype of all affected siblings overlaps well with previously reported patients, suggesting that NM_015465.5: c.3162_3164del (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) is a novel GEMIN5 pathogenic variant. Overall, our data expands the molecular and clinical phenotype of the recently described neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) syndrome.

Expanding the clinical phenotype and genetic spectrum of GEMIN5 disorders: Early‐infantile developmental and epileptic encephalopathies

“…We analyzed the genotype‐phenotype relationship in all reported GEMIN5 pathogenic variants with detailed clinical phenotypes. Previously, 45 kinds of GEMIN5 variants in 48 patients have been reported in 5 published papers (Francisco‐Velilla et al., 2022 ; Ibrahim et al., 2023 ; Kour et al., 2021 ; Rajan et al., 2022 ; Saida et al., 2021 ). Including our 2 patients, a total of 49 variants in 50 patients were collected and analyzed.…”

“…Brain abnormalities are the most common clinical manifestation of GEMIN5 ‐related neurodevelopmental disorders. Only one fifth of patients had seizures before 1 year old, mostly in the neonatal period (Francisco‐Velilla et al., 2022 ; Ibrahim et al., 2023 ; Kour et al., 2021 ; Rajan et al., 2022 ; Saida et al., 2021 ). Seizures in the neonatal period are linked to genetic and structural congenital abnormalities, potentially worsening the condition (Zuberi et al., 2022 ).…”

“…Seizures in the neonatal period are linked to genetic and structural congenital abnormalities, potentially worsening the condition (Zuberi et al., 2022 ). Most GEMIN5 gene mutation patients show cranial structural abnormalities, hinting at a link between seizures and disorder severity (Francisco‐Velilla et al., 2022 ; Ibrahim et al., 2023 ; Kour et al., 2021 ; Rajan et al., 2022 ; Saida et al., 2021 ). In our study, we found that both cases had neonatal epilepsy onset, burst suppression on EEG, and multiple seizure forms.…”

“…WD40 repeat domain is involved in the recognition of snRNAs (Francisco‐Velilla et al., 2022 ). TRP‐like domain with 17 helices that oligomerizes as a canoe‐shaped homodimer is vital for protein architecture and activity (Ibrahim et al., 2023 ). RBS1–RBS2 exerts multiple cellular functions such as RNA‐binding specificity and affinity, as well as translation repression and control of the protein stability (Embarc‐Buh et al., 2021 ; Jin et al., 2016 ; Moreno‐Morcillo et al., 2020 ).…”

“…Clinically, variants in GEMIN5 have been associated with neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) syndrome (OMIM#619333) (Ibrahim et al., 2023 ), neurodevelopmental disorder characterized by cerebellar atrophy, developmental and cognitive delay, ataxia, motor dysfunction, and hypotonia. The association between GEMIN5 variants and epilepsy has not been fully understood and given enough attention.…”