The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

Abstract

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

Figure 1

Structure of the KANSL1 gene and protein and distribution of the SNVs. (a) Gene structure of KANSL1 (NG_032784.1). White boxes indicate exons, connecting lines indicate introns (not drawn on scale), and grey boxes represent untranslated regions (UTRs). SNVs are annotated at the cDNA followed by the number of cases (if >1). (b) Linear protein structure of KANSL1 indicating the different domains and motifs. The KANSL1 protein is mainly unstructured, except for a coiled-coil domain (CC), a possible Zinc finger domain (ZN), a WDR5 interacting motif (WIN), and a PEHE domain. Amino-acid changes are shown above the protein with arrows indicating their position. The two variants that were previously described in the medical literature are shown in red.

Figure 2

Clinical photographs of individuals with KdVS due to a 17q21.31 deletion. Facial photographs of (a) case 5; (b) case 7; (c) case 10; (d) case 11; (e) case 12; (f) case 14; (g) case 16; (h) case 17; (i) case 18; (j) case 22; (k) case 24 front view; (l) case 24 side view; (m) case 25; (n) case 26; (o) case 28; (p) case 29; (q) case 30; (r) case 31; (s) case 32; and (t) case 33. A written informed consent was obtained for publication of clinical photographs in the medical literature.

Figure 3

Clinical photographs of individuals with KdVS due to a pathogenic KANSL1 variant. Facial photographs of (a) case 35; (b) case 36 front view; (c) case 36 side view; (d) case 38; (e) case 39; (f) case 40 age 2 years; (g) case 40 age 7 years; (h) case 41 (i) case 42 front view; (j) case 42 side view; (k) case 43 side view; (l) case 43 front view; (m) case 44; (n) case 45 side view; and (o) case 45 front view. A written informed consent was obtained for publication of clinical photographs in the medical literature.