Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers

Abstract

Intellectual disability (ID), which affects around 2-3% of the general population, is classically divided into syndromic and nonsyndromic forms, with several modes of inheritance. Nonsyndromic autosomal recessive ID (NS-ARID) appears extremely heterogeneous with numerous genes identified to date, including inborn errors of metabolism. The TUSC3 gene encodes a subunit of the endoplasmic reticulum (ER)-bound oligosaccharyltransferase complex, which mediates a key step of N-glycosylation. To date, only five families with NS-ARID and TUSC3 mutations or rearrangements have been reported in the literature. All patients had speech delay, moderate-to-severe ID, and moderate facial dysmorphism. Microcephaly was noted in one third of patients, as was short stature. No patients had congenital malformation except one patient with unilateral cryptorchidism. Glycosylation analyses of patients' fibroblasts showed normal N-glycan synthesis and transfer. We present a review of the 19 patients previously described in the literature and report on a sixth consanguineous family including two affected sibs, with intellectual disability, unspecific dysmorphic features, and no additional malformations identified by high-resolution array-CGH. A homozygous truncating intragenic duplication of the TUSC3 gene leading to an aberrant transcript was detected in two siblings. This observation, which is the first reported case of TUSC3 homozygous duplication, confirms the implication of TUSC3 in NS-ARID and the power of the high-resolution array-CGH in identifying intragenic rearrangements of genes implicated in nonsyndromic ID and rare diseases.

Fig. 1

Consanguineous pedigree (a). Pictures of patient 1 (b) and patient 2 (c) showing similar facial dysmorphism

Fig. 2

(a) Sequencing results of the RT-PCR product showing an aberrant N33/TUSC3 transcript. (b) Structure of the aberrant N33/TUSC3 transcript—underlined, primer sequences; in bold, exon 7 and exon 2 sequences; third line, amino-acid translation; in red, amino-acid translation of the intergenic included region leading to a premature stop codon; 4th line, amino-acid position. (c) Nucleotide sequence of the chr8:15432761–15423779 region analyzed with Human Splicing Finder—underlined, branch site, splice acceptor site, and splice donor site consensus sequences; in italics, CT-rich region; in bold, predicted ESE; in gray, 95 bp intergenic included region

Fig. 3

Schematic representation of the mutations in TUSC3 reported in the literature and in our patients