Coffin-Siris Syndrome 10

A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-10 (CSS10) is caused by heterozygous mutation in the SOX4 gene (184430) on chromosome 6p22.

Description

Coffin-Siris syndrome-10 is characterized by mild to severe intellectual disability, global developmental delay, mild but distinct facial dysmorphism, fifth finger clinodactyly, and small stature. Hypotonia, ventricular septal defect, and spastic quadriparesis may also be present (Zawerton et al., 2019).

For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).

Clinical Features

Zawerton et al. (2019) reported 4 patients with global developmental delay, mild to severe intellectual disability, similar facial dysmorphism with anteverted nares, wide mouth with cupid bow, posteriorly rotated ears, and fifth finger clinodactyly. Patient 1 was a 4-year-old male, born of nonconsanguineous Italian parents. At the time of the report, his height was at the 10th percentile, weight at the 8th percentile, and head circumference at the 1st percentile, with acquired microcephaly. He walked at 27 months of age and said his first words at 4 years. His IQ was 68. He developed seizures at 3.5 years of age that were difficult to control. He had hypotonia, ventricular septal defect, strabismus, epicanthus of the left eye, and stellate irides. He had feeding difficulties, being unable to eat solid food, and had severe constipation. Patient 2 was an 11-year-old male born to nonconsanguineous parents of Scottish and Hungarian ancestry. He had bilateral vertical talus, which was surgically corrected in infancy, as well as laryngomalacia. He lost his ability to roll and bear weight suddenly at age 10 months. He developed spastic quadriparesis. Brain MRIs performed at 15 months and 6 years showed progressive cerebellar atrophy, with patchy cerebral white matter changes. He had progressive microcephaly, severe intellectual disability, and had never walked or talked. Secondary dentition was markedly delayed. Dysmorphic features included trigonocephaly with a mild metopic ridge, bilateral epicanthal folds, infraorbital folds. Patient 3 was a 6-year-old female. She had speech delay, with only single words at 3 years. She had very mild learning disabilities and was not receiving extra help. She was small for her age, and facial features included deep-set eyes, infraorbital grooves, flat nasal bridge. Fifth toenails were dysplastic. Patient 4 was a 6-year-old female with height and weight at the 3rd percentile and normal head circumference. She walked at 21 months and said her first words at 24 months. Her IQ was 52. Facial features included deep-set eyes, infraorbital creases, and malar flattening.

Molecular Genetics

Zawerton et al. (2019) reported 4 patients with heterozygous de novo mutations in the SOX4 gene (184430.0001-184430.0004). All variants clustered in the highly conserved SOX family-specific HMG domain. In silico tools predicted that each variant affected a distinct structural feature of this DNA-binding domain, and functional assays demonstrated that the SOX4 proteins carrying these variants were unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. All variants described occurred in SOX4 residues conserved through zebrafish, and missense variants at equivalent residues of other SOX family members also cause disease.