Alternative titles; symbols
SNOMEDCT: 774068004; ORPHA: 412069; DO: 0070055;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.11-p35.3 | Xia-Gibbs syndrome | 615829 | Autosomal dominant | 3 | AHDC1 | 615790 |
A number sign (#) is used with this entry because of evidence that Xia-Gibbs syndrome (XIGIS) is caused by heterozygous mutation in the AHDC1 gene (615790) on chromosome 1p36.
Xia-Gibbs syndrome (XIGIS) is characterized by impaired intellectual development with absent or poor expressive language, obstructive sleep apnea, mild dysmorphic features, and brain abnormalities (Xia et al., 2014). Patients with XIGIS can have a broad clinical spectrum with multisystemic involvement in addition to neurologic manifestation (Ritter et al., 2018).
Xia et al. (2014) reported 4 unrelated children with impaired intellectual development. All had failure to thrive, hypotonia, and delayed psychomotor development with absent or poor expressive language. Mild dysmorphic features were present, including low-set or protuberant ears, flat nasal bridge, esotropia, hypertelorism, up- or downslanting palpebral fissures, and micrognathia. All also had obstructive sleep apnea, and 3 had laryngomalacia or tracheomalacia. Brain MRI showed hypoplasia of the corpus callosum, simplified gyral pattern, and delayed myelination; 2 patients had a retrocerebellar cyst.
Yang et al. (2015) described 7 unrelated individuals, aged 2 to 16 years, with de novo mutations in the AHDC1 gene. All 7 patients had developmental delay, 6 had hypotonia, 6 had dysmorphisms, and 5 had growth or feeding issues. All 6 patients who were assessed had cognitive delay. Five patients had ataxia and 2 had autism. Five patients had brain abnormalities, including corpus callosum abnormalities, subependymal cysts, and/or hypomyelination. One patient each had omphalocele, left central macular dystrophy, and clubfoot with pes cavus. One patient had sagittal craniosynostosis, cochlear nerve dysfunction, and hypermobile joints.
Garcia-Acero and Acosta (2017) reported an 8-year-old girl with hypotonia, developmental delay, and dysmorphic features, including midface hypoplasia, hypertelorism, micrognathia, and upslanting palpebral fissures. She also had laryngomalacia, which required surgical intervention. Brain MRI showed frontal and temporal cortical atrophy with loss of posterior ventricular white matter.
Ritter et al. (2018) reported 5 patients, aged 8 months to 24 years, with speech and motor developmental delay. Four patients had hypotonia and 1 patient (patient 5) had hypertonia. The 4 oldest patients had mildly to severely impaired intellectual development and growth or feeding issues. Three patients had anatomic upper airway obstruction. Four patients had joint laxity, 2 had scoliosis, and 1 had lumbar lordosis. Structural brain abnormalities included corpus callosum abnormalities (patients 1, 4, and 5), mild cerebral atrophy (patient 4), and ventriculomegaly, diffuse cerebral atrophy, and a small pituitary (patient 3). Patient 1 had bicoronal craniosynostosis, which was surgically corrected. Ritter et al. (2018) concluded that individuals with Xia-Gibbs syndrome can have a broad clinical spectrum with multisystemic involvement in addition to neurologic manifestations.
Gumus (2020) reported a 2-year-old Turkish girl who had bilateral coronal craniosynostosis surgically repaired in infancy. She had seizures beginning at 3 days of life, and EEGs taken at different times showed multifocal and generalized high amplitude spike or slow wave activity. Brain MRI showed cystic encephalomalacia, which was prominent in the frontal lobes, T2A and FLAIR enhancement around the cerebral hemisphere, and a thin corpus callosum. She had elevated calcium and phosphorus on several laboratory measurements. Examination at 2 years of age showed microcephaly, brachycephaly, developmental delay, lack of speech, hypotonia, hairy forehead, thin upper lip, strabismus, and almond-shaped eyes. She also had laryngomalacia.
The heterozygous mutations in the AHDC1 gene that were identified in patients with XIGIS by Xia et al. (2014) and Yang et al. (2015) occurred de novo.
Ritter et al. (2018) reported an 8-month-old female with developmental delay, ventricular septal defect, and hypoplastic corpus callosum who was found to have a chromosome microdeletion at 1p36.1-p35.3, which included the ADHC1 gene. The microdeletion was identified on chromosome microarray.
In a girl with XIGIS, Xia et al. (2014) identified a de novo heterozygous truncating mutation in the AHDC1 gene (615790.0001). The mutation was found by whole-exome sequencing. Targeted sequencing of the AHDC1 gene in 2,000 additional patients identified 3 patients with a similar disorder who had de novo heterozygous truncating mutations (615790.0002-615790.0003). Functional studies of the variants were not performed.
Yang et al. (2015) described 7 unrelated individuals with XIGIS who had de novo truncating mutations in the AHDC1 gene. The patients were identified after whole-exome sequencing in 2,157 patients with intellectual disability or developmental delay; they were confirmed by Sanger sequencing. Six of the mutations were novel and 1 (615790.0001) was previously reported. Functional studies were not performed.
Garcia-Acero and Acosta (2017) identified a de novo heterozygous mutation in the AHDC1 gene (615790.0004) in an 8-year-old Colombian girl with XIGIS. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not performed.
Ritter et al. (2018) reported 4 additional patients with XIGIS and novel de novo truncating mutations in exon 6 of the AHDC1 gene. The mutations were identified by whole-exome sequencing. Functional studies were not performed.
Garcia-Acero, M., Acosta, J. Whole-exome sequencing identifies a de novo AHDC1 mutation in a Colombian patient with Xia-Gibbs syndrome. Molec. Syndromol. 8: 308-312, 2017. [PubMed: 29230160] [Full Text: https://doi.org/10.1159/000479357]
Gumus, E. Extending the phenotype of Xia-Gibbs syndrome in a two-year-old patient with craniosynostosis with a novel de novo AHDC1 missense mutation. Europ. J. Med. Genet. 63: 103637, 2020. [PubMed: 30858058] [Full Text: https://doi.org/10.1016/j.ejmg.2019.03.001]
Ritter, A. L., McDougall, C., Skraban, C., Medne, L., Bedoukian, E. C., Asher, S. B., Balciuniene, J., Campbell, C. D., Baker, S. W., Denenberg, E. H., Mazzola, S., Fiordaliso, S. K., Krantz, I. D., Kaplan, P., Ierardi-Curto, L., Santani, A. B., Zackai, E. H., Izumi, K. Variable clinical manifestations of Xia-Gibbs syndrome: findings of consecutively identified cases at a single children's hospital. Am. J. Med. Genet. 176A: 1890-1896, 2018. [PubMed: 30152016] [Full Text: https://doi.org/10.1002/ajmg.a.40380]
Xia, F., Bainbridge, M. N., Tan, T. Y., Wangler, M. F., Scheuerle, A. E., Zackai, E. H., Harr, M. H., Sutton, V. R., Nalam, R. L., Zhu, W., Nash, M., Ryan, M. M., and 12 others. De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am. J. Hum. Genet. 94: 784-789, 2014. [PubMed: 24791903] [Full Text: https://doi.org/10.1016/j.ajhg.2014.04.006]
Yang, H., Douglas, G., Monaghan, K. G., Retterer, K., Cho, M. T., Escobar, L. F., Tucker, M. E., Stoler, J., Rodan, L. H., Stein, D., Marks, W., Enns, G. M., and 9 others. De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay. Cold Spring Harbor Molec. Case Stud. 1: a000562, 2015. Note: Electronic Article. [PubMed: 27148574] [Full Text: https://doi.org/10.1101/mcs.a000562]