Mental Retardation, Autosomal Recessive 55

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-55 (MRT55) is caused by homozygous mutation in the PUS3 gene (616283) on chromosome 11q24.

Clinical Features

Shaheen et al. (2016) reported 3 sisters, born of consanguineous Saudi Arabian parents, with severe nonsyndromic intellectual disability. All had failure to thrive and global developmental delay associated with small head circumference (range, -2.1 to -3.3 SD) apparent since infancy. At ages 15.5, 12, and 3.3 years, intellectual disability was profound (IQ of 20 to 30). Other common features included coarse facies, strabismus, gray sclerae, and Mongolian spots. The oldest could only ambulate with assistance, and the youngest had axial and appendicular hypotonia. Only 1 patient had well-controlled seizures with onset at age 10 months. Brain imaging showed variable abnormalities in the 3 girls, including ventriculomegaly, arachnoid cysts, cerebral atrophy, T2-weighted signal abnormalities in the subcortical white matter, and dysgenesis of the corpus callosum.

Abdelrahman et al. (2018) reported a 4-year-old boy, born of consanguineous Palestinian parents, with global developmental delay, impaired intellectual development, microcephaly (-2.8 SD), generalized hypotonia, atonic seizures with cyanosis, and sensorineural hearing loss. He was able to control his head and turn over but unable to sit. He was nonverbal. Brain imaging at age 2 years showed dilated lateral ventricles, multiple areas of brain atrophy, and thin corpus callosum.

Inheritance

The transmission pattern of MRT55 in the family reported by Shaheen et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sisters, born of consanguineous Saudi Arabian parents, with MRT55, Shaheen et al. (2016) identified a homozygous truncating mutation in the PUS3 gene (R435X; 616283.0001). The mutation, which was found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the family. Studies of patient cells showed that the mutation caused a loss of enzyme function.

In a retrospective review of multicenter whole-exome sequencing results of an unselected cohort of Saudi patients with various phenotypes, Alfares et al. (2017) identified homozygosity for the previously identified R435X mutation in the PUS3 gene in a patient (patient 121) with autosomal recessive mental retardation. No additional clinical features were provided. The mutation was not found in the ESP or ExAC databases or in 102 ethnically matched controls.

In a 4-year-old boy, born of consanguineous Palestinian parents, with MRT55, Abdelrahman et al. (2018) identified a homozygous frameshift mutation in the PUS3 gene (616283.0002). The mutation was identified by whole-genome trio-based analysis.