A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF) is caused by heterozygous mutation in the SOX4 gene (184430) on chromosome 6p22.

Intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF) is characterized by mildly to severely impaired intellectual development, 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).

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.

Angelozzi et al. (2022) reported 12 patients with IDDSDF and mutations in the SOX4 gene. The phenotype among these patients included a syndromic neurodevelopmental disorder with hypotonia (7/12), borderline to mild intellectual disability (present in all 8 old enough to be assessed), behavioral issues (12/12), speech delay (12/12), and fine (9/12) and gross (9/11) motor delay. Growth parameters and head circumference were normal in most patients (9/12 and 11/12, respectively). Dysmorphic features included a tall forehead that was possibly associated with abnormal metopic suture (5/12), epicanthal folds (4/12), and a wide mouth with full lips and marked philtrum (9/12). Other findings included palatal anomalies (5/12), retrognathia (3/12), and cardiac defects (6/12) consisting of ventricular septal defects and vascular anomalies. Visual impairment was present in 10/12 (mainly myopia and strabismus), and hearing impairment was occasional (3/12). The majority of the more specific features of Coffin-Siris syndrome (e.g., fifth-finger nail hypoplasia, corpus callosum agenesis, and hypertrichosis and hirsutism) were not present.

The heterozygous mutations in the SOX4 that were identified in patients with IDDSDF by Zawerton et al. (2019) occurred de novo.

In 11 patients with IDDSDF reported by Angelozzi et al. (2022), the mutation in the SOX4 gene was shown to be de novo in 8, transmitted by an unaffected mosaic parent in 2, and transmitted by a mildly affected parent in 1.

In 4 patients with IDDSDF, Zawerton et al. (2019) identified de novo heterozygous 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 at SOX4 residues conserved through zebrafish, and missense variants at equivalent residues of other SOX family members also cause disease.

Using exome or genome sequencing in a cohort of patients with a syndromic intellectual developmental disorder, Angelozzi et al. (2022) identified 17 patients with heterozygous variants in the SOX4 gene. Using an in vitro assessment of variant function, 12 of these variants were classified as pathogenic/likely pathogenic because they disrupted SOX4 transcriptional activity, whereas the others were classified as variants of uncertain significance. Among the pathogenic/likely pathogenic variants, 7 were missense variants in the high mobility group (HMG) DNA-binding domain and 5 were stop-gain variants (1 frameshift and 4 nonsense) (see, e.g., 184430.0005-184430.0006). When known, inheritance of the pathogenic/likely pathogenic variants was de novo or from a mosaic unaffected or a nonmosaic affected parent. The phenotype of the patients with pathogenic/likely pathogenic variants was consistent with intellectual developmental disorder with speech delay and dysmorphic facies. The authors noted that although this disorder has also been called Coffin-Siris syndrome-10, the patients they reported lacked the most specific features of Coffin-Siris syndrome (fifth-finger nail hypoplasia, corpus callosum agenesis, and hypertrichosis and hirsutism). Patients with variants of uncertain significance had a milder phenotype.