Rahman Syndrome

A number sign (#) is used with this entry because of evidence that Rahman syndrome (RMNS) is caused by heterozygous mutation in the HIST1H1E gene (142220) on chromosome 6p22.

Description

Rahman syndrome is characterized by mild to severe intellectual disability associated with variable somatic overgrowth manifest as increased birth length, height, weight, and/or head circumference. The overgrowth is apparent in infancy and may lessen with time or persist. The phenotype is highly variable; some individuals may have other minor anomalies, including dysmorphic facial features, strabismus, or camptodactyly. The disorder is thought to result from a defect in epigenetic regulation (summary by Tatton-Brown et al., 2017).

Clinical Features

Tatton-Brown et al. (2017) reported 5 unrelated patients, ranging in age from 1.9 to 16 years, with mild to severe intellectual disability associated with variable somatic overgrowth, including height, weight, and/or head circumference. Two patients showed increased height and/or head circumference early in life, which normalized in the teenage years, whereas the other 3 patients continued to have increased somatic parameters, particularly head circumference (+1.8 to +3.7 SD). Three patients were hypotonic in the neonatal period and 1 was hypertonic. They had similar facial features, including full cheeks, high hairline, and telecanthus. Additional features, each found only in 1 or 2 patients, included kyphoscoliosis, camptodactyly, talipes equinovarus, advanced bone age, dental anomalies, skin nevi, strabismus, astigmatism, and amblyopia. It was unclear if these additional features were related to the mutation or were coincidental.

Molecular Genetics

In 5 unrelated patients with Rahman syndrome, Tatton-Brown et al. (2017) identified 3 different heterozygous truncating mutations in the HIST1H1E gene (142220.0001-142220.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, occurred de novo in 4 families; parental DNA from the fifth family was not available. The mutations not found in the ExAC database or in an in-house database of 11,677 exomes. All of the mutations resulted in the generation of a similar protein truncated in the C-terminal domain, which is involved in chromatin binding and protein-protein interactions. The truncated proteins were predicted to have a reduced net charge compared to the wildtype protein, rendering them likely to be less effective in neutralizing negatively charged linker DNA. Moreover, truncation of the C terminus would likely impede DNA binding and protein-protein interactions. The patients were ascertained from a cohort of 710 individuals with intellectual disability and height and/or head circumference equal to or greater than +2 SD, or 'unspecified overgrowth,' who underwent genetic studies; HIST1H1E mutations accounted for 0.7%. Functional studies of the variants and studies of patient cells were not performed.