ORPHA: 857; MONDO: 0054582;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q23.1 | Townes-Brocks syndrome 2 | 617466 | Autosomal dominant | 3 | DACT1 | 607861 |
A number sign (#) is used with this entry because of evidence that Townes-Brocks syndrome-2 (TBS2) is caused by heterozygous mutation in the DACT1 gene (607861) on chromosome 14q23.
For a discussion of genetic heterogeneity of Townes-Brocks syndrome, see TBS1 (107480).
Webb et al. (2017) studied a family in which 6 members exhibited features overlapping those of Townes-Brocks syndrome. The proband was a 20-month-old girl who was born with imperforate anus, rectovaginal fistula, crossed fused renal ectopia, and vesicoureteral reflux. In addition, her right ear was smaller than the left, and both ears showed overfolding of the superior helix and cupping, which was more pronounced on the right. Her 7-year-old brother also exhibited imperforate anus, as well as hypospadias, crossed fused renal ectopia, vesicoureteral reflux, and overfolding of both ears that was more pronounced on the right and also involved cupping on the right VSports app下载. Their mother had bilateral ear cupping, and spina bifida occulta had been diagnosed in her teen years. The mother's half-sister had severe microtia of the left ear, as did the proband's maternal grandmother, who also had bifid uterus. .
Christians et al. (2023) reported in 11 patients from 8 families with Townes-Brocks syndrome-2. Ten patients had congenital anomalies of the kidney and urinary tract, 4 patients had neurologic abnormalities, 4 patients had skeletal abnormalities, 1 patient had genital anomalies, and 1 patient had distal digestive tract abnormalities V体育官网. One patient (V005-II. 04) had caudal regression syndrome including missing coccyx, sacral dysplasia, syringohydromyelia and anorectal dysgenesis. This patient also had agenesis of the corpus callosum, hydrocephalus and agenesis of the cerebellar vermis. .
The transmission pattern of TBS2 in the family reported by Webb et al. (2017) was consistent with autosomal dominant inheritance.
By whole-exome sequencing in a 3-generation family segregating features of Townes-Brocks syndrome, negative for mutation in the SALL1 gene (602218), Webb et al. (2017) identified heterozygosity for a nonsense mutation in the DACT1 gene (W419X; 607861.0001) that segregated fully with disease and was not found in public variant databases. The authors noted that identification of additional affected individuals with DACT1 mutations was necessary to understand the full spectrum of disease.
In a Kurdish patient with TBS2, Christians et al. (2023) identified a heterozygous mutation in the DACT1 gene (T367K; 607861.0002). The mutation, which was identified by whole-exome sequencing, was shown to be inherited from the patient's unaffected mother. Christians et al. (2023) then sequenced the DACT1 gene in 209 families affected with congenital anomalies of the kidney and urinary tract and identified 8 (3.8%) families with heterozygous mutations. In several cases, the mutation was inherited from an unaffected parent. Christians et al. (2023) noted that incomplete penetrance of renal/urinary tract phenotypes and variable expressivity of extrarenal features were observed in patients who were heterozygous for mutations in the DACT1 gene.
Christians, A., Kesdiren, E., Hennies, I., Hofmann, A., Trowe, M. O., Brand, F., Martens, H., Gjerstad, A. C., Gucev, Z., Zirngibl, M., Geffers, R., Seeman, T., Billing, H., Bjerre, A., Tasic, V., Kispert, A., Ure, B., Haffner, D., Dingemann, J., Weber, R. G. Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2. Hum. Genet. 142: 73-88, 2023. [PubMed: 36066768] [Full Text: https://doi.org/10.1007/s00439-022-02481-6]
Webb, B. D., Metikala, S., Wheeler, P. G., Sherpa, M. D., Houten, S. M., Horb, M. E., Schadt, E. E. Heterozygous pathogenic variant in DACT1 causes an autosomal-dominant syndrome with features overlapping Townes-Brocks syndrome. Hum. Mutat. 38: 373-377, 2017. [PubMed: 28054444] [Full Text: https://doi.org/10.1002/humu.23171]