Mental Retardation, Autosomal Dominant 58

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-58 (MRD58) is caused by heterozygous mutation in the SET gene (600960) on chromosome 9q34.

Clinical Features

Stevens et al. (2018) reported 5 unrelated children with delayed development and intellectual disability with language delay and speech impairment. Some of the patients had motor delay or incoordination, but all could walk. Some patients had minor dysmorphic features, such as facial asymmetry, high palate, dental crowding, hypertelorism, plagiocephaly, small head circumference, large ears, broad nasal bridge, thick lips, and wide mouth. Additional variable nonspecific features included hypotonia and hypermobility; 1 patient had 2 seizures. Brain imaging, performed only in a few patients, was normal.

Inheritance

The transmission pattern of MRD58 in a family reported by Stevens et al. (2018) was consistent with autosomal dominant inheritance. The remaining patients with MRD58 in the study had de novo SET mutations.

Molecular Genetics

In 6 patients, including a mother and son, with MRD58, Stevens et al. (2018) identified heterozygous mutations in the SET gene (see, e.g., 600960.0001-600960.0004). The mutations were found by exome sequencing and the patients were ascertained through collaborative efforts of clinical genetics laboratories. All of the mutations occurred de novo, except in 1 family (the mother and son), and all were predicted to affect the 4 SET transcript isoforms. Stevens et al. (2018) noted that de novo heterozygous loss-of-function SET mutations had previously been found in 3 unrelated patients with intellectual disability in the Deciphering Developmental Disorders Study (2017) and in 1 patient with intellectual disability in a large study by Hamdan et al. (2014) (see 600960.0005). Functional studies of the variants and studies of patient cells were not performed, but all mutations were predicted to result in a loss of function and haploinsufficiency. Stevens et al. (2018) stated that SET plays a role in neurogenesis and neuronal differentiation. The findings suggested that disruption of epigenetic regulatory modules can lead to intellectual disability.