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 Lugtenberg et al. (2017) identified 10 individuals with de novo loss of function variants in WAC (4 nonsense, 1 exonal del, 5 frameshift) in a cohort of 2300 individuals with unexplained intellectual disability (ID) using whole exome sequencing (WES) and subsequent targeted testing. 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: One individual (previously reported by De Ligt 2012) also carried a de novo mutation in the MIB1 gene (autosomal dominant for Left ventricular noncompaction 7, OMIM:615092), and it has been reported twice in ExAC. Moreover, one missense and one nonsense mutation in MIB1 were identified previously and segregated each in two large dominant families with cardiomyopathy, but without ID. Therefore, its contribution as a potential modifier of the more severe phenotype is unlikely.
26264232 DeSanto et al. (2015) used WES and identified 6 patients with idiopathic ID and de novo WAC loss of function mutations (3 nonsense, 2 frameshift). Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioral 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 nonsense variants (patient 1 & 2). NOTE: Patient 4 also has a de novo missense variant in the MED12 gene (X-linked recessive) that is conserved in vertebrates but is predicted to be benign by SIFT and PolyPhen.
28263302 Yuen et al (2017) used whole genome sequencing (WGS) on 5,205 samples from families with ASD and identified 18 new candidate ASD-risk genes including WAC. 1 individual had a de novo frameshift mutation and a phenotype including speech language impairment, hyperactivity, sleep issues, shallow mid facial area, fairly prominent eyelids, hypertelorism, slightly prominent forehead, mildly broad great toe, other toes look short relative to the feet, mild low to mid frequency hearing loss, and EEG - Focal epileptiform discharge in left temporal region.
26795593 Helbig et al. (2016) used WES and subsequent targeted sequencing of 1131 patients with or without epilepsy, identifying a de novo nonsense mutation in a patient with infancy-onset unclassified epilepsy.
25356899 Hamdan et al. (2014) performed WES on 41 probands with moderate or severe ID and their parents and identified a frameshift variant in an individual with moderate ID without any distinguishing features.

Haploinsufficiency phenotype comments:

Additional Evidence: PMID: 25363768 Iossifov et al. 2014 used WES on >2500 families with a proband with ASD and identified a de novo frameshift variant in one individual. PMID: 25533962 Deciphering Developmental Disorders Study (2015) used a genotype-driven approach by studying 1,133 children with severe, undiagnosed developmental disorders. Using WES and array, the authors discovered 12 novel genes associated with developmental disorders including one individual with a variant in the gene WAC.

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

Triplosensitivity phenotype comment:

Currently there is no literature of duplications involving only the WAC gene.