Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants

Abstract

Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.

Fig. 1. Pedigrees of the 14 reported families.

The red arrow indicates the MRXSCJ patients described in this study. The black square/circle indicate symptomatic subjects with KDM5C variants. KDM5C female carriers are indicated as gray circles when mildly affected or white circles when reported as asymptomatic. The stripes in the symbols of individuals II:1 and II:4 of pedigree PD-2616 indicate different clinical conditions. Variants have been named based on the following reference sequences: NM_004187.5 and NP_004178.2 for KDM5C; NM_000147.5 and NP_000138.2 for FUCA1; NM_000828.5 and NP_000819.4 for GRIA3; NM_031407.7 and NP_113584.3 for HUWE1. NT not tested, “wt” wild-type, “v” variant.

Fig. 2. Schematic representation of the KDM5C gene organization, protein domains, and localization of the fourteen variants described in this study.

Gene exons numbered from 1 to 26 (GeneBank reference sequence NM_004187.3) are colored and approximately aligned with the corresponding domains. Nucleotide changes predicted to result in truncating protein products are mapped in the KDM5C exonic sequence and the truncated endpoints are indicated. Different geometric symbols are assigned to the various domain types and indicated by the abbreviations: Pink Trapezium: N-terminal (JmjN; aa 13-81) and C-terminal (JmjC; aa 389-618) Jumonji domains; Light blue hexagon: ARID, AT-rich interaction domain (aa 82-179); Cyan rhombus: Zinc Finger-PHD type, PHD-1 (aa 324-374) and PHD-2 (aa 1185-1250); Green pentagon: Zinc-finger C5HC2 type domain (aa 619-768); Yellow ovals: Spectrin-like domains, SPECL-1 (769-862), -2 (871-978), -3 (981-1090); Orange spheres: predicted helical-rich regions: H1 (1132-1168); H2 (1255-1329); H3 (1398-1428); IDL: putative intrinsically disorder loop (aa 1330-1397); Red: Arginine-rich region (1449-1483). KDM5C missense variants described in this study are mapped to the protein sequence (in bold, blue font, top panels). Other reported missense variants that locate on the same domains are indicated (black font, bottom panels).

Fig. 3. Structural effect of KDM5C missense variants mapping in structural domains.

Cartoon representation of the N-terminal part of KDM5C model (residues 1-915) from AlphaFold with domains colored as indicated in Fig. 2. Since the C-terminal part contains long disordered regions that cannot be modeled and due to the low reliability of the helical domains arrangement, only the model of PHD2 domain has been shown in the picture. Positions of the six amino acid substitutions mapping in the JmjC, ARID, and PHD2 domain are shown as orange spheres in the models, and close-up views of their affected intramolecular bonding with surrounding residues are shown in zoom panels. For p.(D111V) in the ARID domain, the sequence alignment shows the conservation of this mutated position among KDM5 and other ARID-containing proteins.