A founder nonsense variant in NUDT2 causes a recessive neurodevelopmental disorder in Saudi Arab children

Abstract

We identified the homozygous p.Arg12* variant in 5 patients with neurodevelopmental delay, but variation databases list many truncating heterozygous variants for this small 2-exon gene. As most of these affect the protein's C-terminus, loss-of-function mediated pathogenicity may be confined to bi-allelic truncating variants in exon 1 (nonsense-mediated decay!) or in the catalytically active Nudix box.

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort

“…We also examined the group of 12 cases with positive GS diagnosis which previously tested negative by ES performed elsewhere (no raw data or specific testing details were available). Successful GS diagnosis was mainly based on detection of intronic variants (four cases), small indels (four cases), and detection of coding variants in genes that were considered as 'diagnostic' based on observations from our own database (NUDT2 [28], GTPBP2 [29], and NKX6-2 [25]), allowing genetic diagnosis before that published evidence became available.…”

Novel NUDT2 variant causes intellectual disability and polyneuropathy

“…We report three patients from two families with sensorimotor polyneuropathy and intellectual disability due to a newly described pathogenic variant in NUDT2 . While one founder variant in NUDT2 has been reported in cases with intellectual disability, 5,6 the three cases presented here also developed profound neuropathies resulting in distal weakness in addition to intellectual disability.…”

“…We report three patients from two families with sensorimotor polyneuropathy and intellectual disability due to a newly described pathogenic variant in NUDT2. While one founder variant in NUDT2 has been reported in cases with intellectual disability, 5,6 the three cases presented here also developed profound neuropathies resulting in distal weakness in addition to intellectual disability. The previous seven cases described with intellectual disability were of Saudi Arabian origin and were found to have a different founder variant in NUDT2, homozygous nonsense variant NM_001244390.1:c.34C>T (p. Arg12*).…”

“…The previous seven cases described with intellectual disability were of Saudi Arabian origin and were found to have a different founder variant in NUDT2, homozygous nonsense variant NM_001244390.1:c.34C>T (p. Arg12*). 5,6 The first study described the variant in two cases with intellectual disability, hypotonia, and unsteady gait ( Table 1). The second study 6 described five patients from three unrelated families that shared delayed motor and language development, and borderline intelligence, among other features (Table 1) The variant presented here does not appear to be a founder mutation.…”

“…As a diadenosine tetraphosphate (AP 4 A) hydrolase, 2 it is thought to play an important role in a number of cellular processes, including the metabolism of toxic byproducts, DNA replication, and cell proliferation, among others, 3,4 and may be a prognostic marker in breast carcinomas 3 . NUDT2 has been previously associated with intellectual disability in a small number of families, 5,6 suggesting a role in central nervous system development, but no other neurological presentations associated with this gene have been reported. We report three cases from two unrelated families with a novel mutation in NUDT2 that presented with global developmental delay and intellectual disability, but also with length‐dependent sensorimotor polyneuropathies with demyelinating and/or axonal features, expanding the phenotype associated with this gene.…”