ClinGen Dosage Sensitivity Curation Page

4p16.3 terminal (Wolf-Hirshhorn syndrome) region

  • Curation Status: Complete
  • id: ISCA-37429
  • Date last evaluated: 2016-08-11
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 2

Location Information

Select assembly: (NC_000004.11) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description

Haploinsufficiency phenotype comments:

Deletion of the terminal 4p region is associated with Wolf-Hirschhorn syndrome (WHS). The core features (minimal diagnostic criteria) of WHS include a typical craniofacial appearance, growth deficiency, developmental delay/intellectual disability of variable degree, and seizures (or EEG anomalies). WHS is considered to be a contiguous gene deletion syndrome, caused by haploinsufficiency of multiple genes in this region. The region sufficient to cause the core WHS phenotype spans ~1.7 Mb from 331,596 (distal boundary ZNF141, to include distal gene of CR for seizures proposed in Ho et al., 2016 PMID: 26747863; note also ~400 kb deletions may be benign; see South et al., 2008, PMID 18932125) to 2,010,962 (proximal boundary NELFA) in 4p16.3 (hg19), including candidate genes LETM1, WHSC1 and NELFA (formerly WHSC2). Smaller deletions within this region should be evaluated for gene content to determine clinical significance. Larger deletions may be associated with additional clinical findings, including a variety of congenital anomalies and malformations. See GeneReviews, Zollino et al 2008 (PMID 18932124) and South et al 2008 (PMID 18932125) for reviews. NOTE: Previous studies used deletion mapping of patients with variably sized terminal and interstitial deletions in 4p to delineate critical regions for WHS. These proposed regions span from approximately 1.4 to 2.0 Mb in 4p16.3 (hg19): the first critical region (WHSCR) spanned ~165 kb and included candidate genes WHSC1 (3 prime end) and NELFA (formerly WHSC2) (Wright et al 1997; PMID: 9063753); the second critical region, WHSCR-2, fell within a 300-600 kb interval between loci D4S3327 and D4S98-D4S168, and included candidate genes WHSC1 (5 prime end) and LETM1 (Zollino et al., 2003; PMID 12563561).

  • Triplosensitivity score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

A limited number of patients with isolated duplications affecting this region of 4p16.3 are reported in the literature and there is variability in duplication breakpoints across these patients. Therefore the triplosensitivity score of this region is currently a 2. Reports of patients with known or presumed isolated duplications encompassing this region: Schonewolf-Greulich et al., 2013 (PMID 23894085) presented a 3-generation family with a terminal 3 Mb duplication at 4p16.3 (73,645-3,072,968, hg19) segregating with a clinical phenotype that included macrocephaly, tall stature, developmental and speech delay, and minor anomalies. The 4 affected family members were daughter (proband), mother, maternal uncle, and maternal grandmother. The duplicated region was shown to be localized to 21p, presumed to represent an inherited unbalanced translocation. Carmany et al., 2011 (PMID 21412978) presented a patient with a 2.3 Mb duplication spanning from 45,881-2,327,204 (hg19, converted from hg18), inferred from oligo aCGH analysis performed for a sibling who carried the reciprocal deletion, due to an unbalanced translocation 4;17. The concomitant 17q25.3 deletion was 315 kb, and was proposed as likely benign. The clinical findings in this patient included speech delay, developmental delay, borderline hypertelorism, dysmorphic facial features and no seizures. Additional reports of patients with smaller duplications in this region: Hannes et al., 2010 (PMID 20197130) identified by BAC array a 560 kb de novo duplication overlapping the WHS critical region 2 and spanning from ~1.46 to 1.91 Mb. The duplicated region was shown to be localized to medial 4q, apparently resulting from an intrachromosomal rearrangement (pericentric inversion). The patient presented with seizures, developmental delays and intellectual disabilities, glaucoma of the left eye, hypotonia, finger contractions and a distinct facial gestalt, some of which overlap with the 4p deletion phenotype. The authors noted the possibility for gene disruption due to the pericentric inversion. Cyr et al., 2011 (PMID 21815251) described a 506 kb de novo duplication from 1,336,373-1,862,819 (hg19, converted from hg18) including the candidate gene LETM1, but not WHSC1 or NELFA. The patient presented with developmental delays, intellectual disabilities, macrocephaly, irregular iris pigmentation-heterochromia, seizures, and dysmorphic features including abnormal hands, prominent glabella, low-set ears, and short neck. Palumbo et al., 2015 (PMID 25774220) reported a 400 kb duplication (inheritance unknown) from 1,405,662-1,798,461 (hg19) that overlaps the distal portion of previous 4p16.3 microduplications and does not include candidate genes LETM1, WHSC1 or NELFA. The patient presented with dysmorphic facial features, attention deficit hyperactivity disorders, learning difficulties, speech and cognitive delays, overgrowth and musculoskeletal anomalies.