Alternative titles; symbols
HGNC Approved Gene Symbol: WAC
SNOMEDCT: 1187247007;
Cytogenetic location: 10p12.1 Genomic coordinates (GRCh38) : 10:28,532,779-28,623,112 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.1 | Desanto-Shinawi syndrome | 616708 | Autosomal dominant | 3 |
WAC localizes to nuclear speckles and is predicted to be involved in RNA processing (Xu and Arnaout, 2002).
By sequencing clones from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) obtained a partial WAC clone, which they designated KIAA1844. RT-PCR analysis detected robust WAC expression in all adult and fetal tissues examined, with highest expression in whole adult brain and fetal liver. Whole fetal brain showed much lower WAC expression than whole adult brain. Within specific adult brain regions, highest expression was detected in caudate nucleus, substantia nigra, and thalamus.
Xu and Arnaout (2002) cloned mouse Wac, which encodes a deduced 646-amino acid protein with a calculated molecular mass of 71 kD. Wac contains an N-terminal WW domain and a C-terminal coiled-coil region. The WW domain of Wac is similar to WW domains involved in RNA processing. Wac is also rich in serine, threonine, and proline, including many potential phosphorylation sites, and has dipeptide repeats of alternately charged amino acids, including RD repeats. By EST database analysis, Xu and Arnaout (2002) identified human and zebrafish orthologs of mouse Wac. The mouse and human WAC proteins share 94% identity. Following transfection in human and monkey kidney cells, mouse Wac colocalized in nuclear speckles with SC35 (SRSF2; 600813), a component of the pre-mRNA splicing complex.
By genomic sequence analysis, Xu and Arnaout (2002) mapped the WAC gene to chromosome 10p12.1-p11.2.
In 6 children, including 2 sibs, with DeSanto-Shinawi syndrome (DESSH; 616708), DeSanto et al. (2015) identified 5 different heterozygous truncating mutations in the WAC gene (615049.0002-615049.0006). The mutation in the sibs was postulated to have resulted from germline mosaicism in 1 of the parents; the remaining mutations occurred de novo. The mutations were found by whole-exome sequencing; functional studies were not performed, but all were predicted to result in a loss of function. The disorder was characterized by global developmental delay apparent in most since infancy, characteristic dysmorphic features, ocular and gastrointestinal abnormalities, and behavioral abnormalities. DeSanto et al. (2015) noted that Hamdan et al. (2014) had identified a de novo heterozygous truncating mutation in the WAC gene (615049.0001) in a woman with moderate intellectual disability. That patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing.
In a woman (patient 762.297) with features consistent with DeSanto-Shinawi syndrome (DESSH; 616708), Hamdan et al. (2014) identified a de novo heterozygous 4-bp deletion (c.263_266delAGAG, NM_016628.4) in the WAC gene, resulting in a frameshift and premature termination (Glu88GlyfsTer103). The patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing. Clinical details were sparse, but the child was noted to have moderate intellectual disability without any distinguishing features on clinical examination or brain imaging.
In 2 Caucasian sisters with DeSanto-Shinawi syndrome (DESSH; 616708), DeSanto et al. (2015) identified a de novo heterozygous c.1721G-A transition (c.1721G-A, NM_016628.4) in exon 12 of the WAC gene, resulting in a trp574-to-ter (W574X) substitution. The mutation was not detected in the unaffected parents, strongly suggesting germline mosaicism. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project or ExAC databases.
In a girl with DeSanto-Shinawi syndrome (DESSH; 616708), DeSanto et al. (2015) identified a de novo heterozygous 2-bp duplication (c.267_268dup, NM_016628.4) in exon 3 of the WAC gene, resulting in a frameshift and premature termination (Asp90GlyfsTer103). The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project or ExAC databases. (In the article by DeSanto et al. (2015), the protein change was given as Asp90GlyfsTer103 in the text and Figure 2, but as Asp90TrpfsTer103 in Table 1.)
In a boy of Mexican descent with DeSanto-Shinawi syndrome (DESSH; 616708), DeSanto et al. (2015) identified a de novo heterozygous c.374C-A transversion (c.374C-A, NM_016628.4) in exon 4 of the WAC gene, resulting in a ser125-to-ter (S125X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project or ExAC databases.
In a girl with DeSanto-Shinawi syndrome (DESSH; 616708), DeSanto et al. (2015) identified a de novo heterozygous c.1852C-T transition (c.1852C-T, NM_016628.4) in exon 13 of the WAC gene, resulting in a gln618-to-ter (Q618X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project or ExAC databases.
In a girl of European descent with DeSanto-Shinawi syndrome (DESSH; 616708), DeSanto et al. (2015) identified a de novo heterozygous 1-bp deletion (c.112delA, NM_016628.4) in the WAC gene, resulting in a frameshift and premature termination (Ser38AlafsTer154). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project or ExAC databases.
DeSanto, C., D'Aco, K., Araujo, G. C., Shannon, N., DDD Study, Vernon, H., Rahrig, A., Monaghan, K. G., Niu, Z., Vitazka, P., Dodd, J., Tang, S., and 9 others. WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome. J. Med. Genet. 52: 754-761, 2015. [PubMed: 26264232] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103069]
Hamdan, F. F., Srour, M., Capo-Chichi, J.-M., Daoud, H., Nassif, C., Patry, L., Massicotte, C., Ambalavanan, A., Spiegelman, D., Diallo, O., Henrion, E., Dionne-Laporte, A., Fougerat, A., Pshezhetsky, A. V., Venkateswaran, S., Rouleau, G. A., Michaud, J. L. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10: e1004772, 2014. Note: Electronic Article. [PubMed: 25356899] [Full Text: https://doi.org/10.1371/journal.pgen.1004772]
Nagase, T., Nakayama, M., Nakajima, D., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 8: 85-95, 2001. [PubMed: 11347906] [Full Text: https://doi.org/10.1093/dnares/8.2.85]
Xu, G. M., Arnaout, M. A. WAC, a novel WW domain-containing adapter with a coiled-coil region, is colocalized with splicing factor SC35. Genomics 79: 87-94, 2002. [PubMed: 11827461] [Full Text: https://doi.org/10.1006/geno.2001.6684]