ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 10p12.1|10p12.1-p11.2
  • GRCh37/hg19 chr10: 28,821,517-28,912,041
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr10: 28,532,772-28,623,112
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000010.10) (NC_000010.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
26757981 By WES and subsequent targeted sequencing a cohort of 2300 individual with unexplained ID, Lugtenberg et al 2017 identified 10 individuals with de novo LOF variants in WAC (4 NS, 1 exonal del, 5 fs). showed distinct phenotypic overlap. All, but one individual, had mild-to-severe ID accompanied by language and motor delay. In addition, individuals showed a variety of neurological problems including hypotonia (6/9), with remarkable manifestation in the oral region resulting in dysarthria, and behavioral problems (10/10). The latter recurrently included autism (4/9), anxiety (3/10), concentration disorder (4/10) and/or sleep disturbance (6/10). Other overlapping features consisted of unexplained reduced vision (3/9) and respiratory problems (7/9) with recurrent respiratory infections reported most often (5/7). Notably, all individuals had overlapping facial dysmorphisms consisting of a square shape of the face, deep set eyes, long palpebral fissures, broad mouth and broad chin........... [NOTE: (1). individual 1 (previously reported by De Ligt 2012) also carrier a de novo mutation in MIB1 gene (AD for Left ventricular noncompaction 7,OMIM:615092). But it has been reported twice in ExAC. Moreover, one MS and one NS mutations in MIB1 were identified previously and segregated each in two large dominant families with cardiomyopathy, but without ID. Therefore, its contribution as potential modifier of the more severe phenotype is unlikely]
26264232 DeSanto et al. 2015 WES identified 6 patients with idiopathic ID and de novo WAC LOF mutations (3 NS, 2 fs). Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted.........germline mosaicism has been suggested in genotypically normal parents of affected siblings carrying NS variant (patient 1 & 2)........... [NOTE: patient 4 also has a de novo MS in MED12 gene (XLR) that conserved in vertebrates but is predicted to be benign by SIFT and PolyPhen. ]
28263302 Yuen et al 2017 WGS of 5,205 samples from families with ASD identified 18 new candidate ASD-risk genes including WAC. 1 individual had de novo fs mutation and features including Speech Language Impairment; hyperactivity; sleep issues; Shallow mid facial area; fairly prominent eyelids; slightly hyperteloric; Forehead slightly prominent; Great toe mildly broad, other toes look short relative to the feet; mild low to mid frequency hearing loss, right ear; EEG - Focal epileptiform discharge in left temporal region.

Haploinsufficiency phenotype comments:

more papers.........(1). PMID:26795593, By result comparison of WES and subsequent targeted seq of 1131 patients with or without epilepsy, Helbig et al. 2016 identified a de novo NS mutation is a patient with infancy-onset unclassified epilepsy..........(2). PMID:25363768, Iossifov et al. 2014 WES of >2500 family with an autistic Proband identified a de novo fs mutation in one individual.......(3) PMID: 25356899, Hamdan et al 2014 WES of 41 probands with moderate or severe ID and their parents identified a fs mutation in a individual with moderate ID without any distinguishign features......(4) PMID:26325558. WES 95 Proabnd with ASD or ID identified a patient with de novo fs variant.......... (5)PMID:25533962.The Deciphering Developmental Disorders Study. genotype-driven approach by studying 1,133 children with severe, undiagnosed developmental disorders, and their parents by WES and array, discovered 12 novel genes associated with developmental disorders. there is one patient with de novo WAC mutation ( listed in GeneReviews, but could not access the actual data about the patient.)

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

could not find any literature of duplication that involves only WAC gene