Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants

Abstract

Intellectual disability (ID) is a highly heterogeneous genetic condition with more than a thousand genes described so far. By exome sequencing of two consanguineous families presenting hallmark features of ID, we identified two homozygous variants in two genes previously associated with autosomal recessive ID: NDST1 (c.1966G>A; p.Asp656Asn) and METTL23 (c.310T>C; p.Phe104Leu). The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the secondary structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic NDST1 and METTL23 variants in two cases of autosomal recessive ID further highlight the importance of these genes in proper brain function and development.

Keywords: METTL23; NDST1; autosomal recessive intellectual disability; exome sequencing.

Figure 1

(A) Pedigree of family B, exhibiting autosomal recessive inheritance. (B) Sanger sequencing results of family (B). The red arrow indicates the localization of the variant. (C) Conservation of Phe104 across different species. (D) Gene structure of METTL23. Known variants are indicated on the gene structure. The c.310T>C variant is shown in red. (E) The modeled structure in complex with the SAH ligand, which was superimposed according to the METTL21C structure. (F) The Phe104Leu mutation in the modeled structure. (G) Same as (E) without showing the molecular surface. (H) The superimposition of the SAH and SAM ligands from the METTL21A, METTL21B and METTL21C. (I) The molecular surface of the modeled structure of METTL23. (J) The superimposition between the modeled METTL23 and crystal structure of METTL21C. (K) The molecular surface of METTL21C. (L) The structure and molecular surface of METTL21C.

Figure 2

(A) Pedigree of family A, exhibiting an autosomal recessive inheritance. Males are represented by squares, females by circles. Filled and unfilled symbols illustrate the affected and unaffected individuals, respectively. A diagonal line over a circle or square represents deceased individuals. Consanguinity is represented by double lines (=). (B) Sanger sequencing results of family A. The red arrow indicates the localization of the variant. (C) Conservation of Asp656 across different species. The sequence shown is part of the heparin sulfate N-sulfotransferase domain. (D) Gene structure and protein domains of NDST1. Known variants are indicated on the gene structure. The c.1966G>A variant is shown in red. (E) Modeling the NSDT1 dimer structure using 3-O-sulfotransferase as a template (colored as magenta). Two copies of NSDT1 (green and cyan) are superimposed to the two domains of 3-O-sulfotransferase. The Asp656Asn mutation site is shown as a red stick model. (F) The dimer structure of NSDT1 without the 3-O-sulfotransferase template. The Asp656Asn mutation lies on the binding interface. (G) The proximal interaction between Asp656Asn and the Asp602 and Arg603 residues on the other interacting domain.