SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome

Abstract

Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to SETD5 gene mutations, falls into this group of disorders. KBG syndrome, caused by ANKRD11 gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A de novo deletion of 116 kb partially involving SETD5 and two de novo frameshift variants in SETD5 were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider SETD5 gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS.

Keywords: 3p25 microdeletion syndrome; KBG syndrome; MRD23; SETD5 haploinsufficiency; WES.

Figure 1

Clinical features of patients 2 and 3. (A) P2 as an infant and at the age of 2 (B,C), 6 (D,E), and 8 (F,G) years. (A–G) Facial dysmorphisms of P2 evolving with age include low anterior hairline, thick eyebrows, long palpebral fissures, and bulbous nose. (H) P3 at 12 months, and at the age of 3 (I) and 16 years (J,L–N). (H–J, L–N) Facial dysmorphisms of P3 evolving with age include triangular face, low anterior, and posterior hairline (L), synophris, long palpebral fissures, anteverted nares, long philtrum, thin upper lip, low set and overfolded ears, overcrowded, and misplaced teeth (N). Other findings such as pectus excavatum, flat foot, and slender habitus can be noticed as well (J). (K) P3 chest radiograph revealing accessory cervical ribs.

Figure 2

Physical map of the 3p25.3 genomic region and detected variants. In the upper part, the physical map of the 3p25.3 genomic region shows the deletion (red bar) detected in patient 1 and the two SNVs detected in patients 2 and 3. The 3pter-p25 deletion syndrome critical region is indicated by a black bar, the RefSeq genes are depicted in dark blue, and the OMIM disease genes in green. The image is a modification of a version obtained from the UCSC Genome Browser (human genome assembly GRCh37/hg19). In the lower part, an array CGH profile shows the 3p25.3 deletion identified in patient 1, and Sanger sequencing confirmation of the two SNVs detected in patient 2 and patient 3. Genomic positions refer to the human genome assembly GRCh37/hg19.