Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn Syndrome

Abstract

Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

Figure 1

Photographs of patients 1–3. (a, b) Patient 1 at age 15 months (a) and 2 years 9 months (b). (c) Patient 2 at age 7. (d, e) Patient 3 at age 12 months (d) and 18 months (e).

Figure 2

3D facial analysis of patient 1 (a, c) and patient 3 (b, d). (a, b) Heat-mapped face signatures showing normalized face shape differences (displacement of surface points orthogonal to face surface and parallel to three axes) compared with matched control mean. The red/green/blue coloring reflects displacement orthogonal to the surface in the first signature (red/green/blue=contraction/coincidence/expansion) and in the three axial signatures parallel to the colored arrows with green=no displacement and maximal red-blue hues reflecting 2 SDs or more. (c, d) Comparison of subject profiles with WHS patients and controls by blinded closest mean classification. X axis—similarity to average faces of sex-matched control (−1) and WHS (+1) subgroups. Y axis – outlier status (distance from control-WHS mean axis). For patient 1: n(WHS)=24 and n(control)= 38. For patient 3: n(WHS)=35 and n(control)= 56. A full color version of this figure is available at the European Journal of Human Genetics journal online.

Figure 3

Genomic region of 4p16.3 involved in the deletions of patients 1–3. Snapshot of genomic region 1.740–2.125 Mb of chr. 4 displayed using the UCSC genome browser (GRCh37/hg19) showing the location of deletions of patients 1–3. The RefSeq Genes track shows the mapped location and exon/intron structure of gene transcripts from the NCBI RNA reference sequences collection of known protein-coding (dark-colored) and non-protein-coding (light-colored) genes. Non-coding exons are displayed as half the height of coding exons and the direction of transcription with arrowheads. The CpG islands track shows the location of predicted clusters of methylated CG dinucleotides, which are common near transcription start sites and may be associated with promoter regions. The ENCODE layered H3K4Me3 and H3K27Ac tracks show the location and levels of enrichment of H3K4Me3 and H3K27Ac histone marks, which are molecular correlates of promoters and enhancers, respectively.