Mental Retardation, Autosomal Dominant 23

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-23 (MRD23) is caused by heterozygous mutation in the SETD5 gene (615743) on chromosome 3p25.

Clinical Features

Grozeva et al. (2014) reported 7 unrelated boys with moderate to severe intellectual disability. All showed delayed psychomotor development in infancy and poor speech development, but all were able to talk and communicate their needs. Five of the 7 had behavioral abnormalities, including obsessive-compulsive behavior, hand-flapping, and features of autism. Older children attended special schools or had educational support. Dysmorphic features were highly variable without a consistent pattern. However, features observed in 3 or more affected patients included synophrys or eyebrow anomalies, brachycephaly, low hairline, depressed nasal bridge, prominent high nasal root, tubular nose, upslanting palpebral fissures, long and smooth philtrum, micrognathia, thin upper lip, and crowded teeth. Several patients had chewing difficulties or dribbling. Variable skeletal abnormalities, such as scoliosis, kyphosis, lordosis, and leg-length discrepancies were also reported. None had seizures, microcephaly, or growth retardation. Grozeva et al. (2014) noted that some of the features overlapped those observed in patients with the 3p25 microdeletion syndrome (613792), and that the SETD5 gene lies within the 3p25 critical region. However, 3p25 deletion syndrome was not suspected clinically in any of the 7 patients.

Kuechler et al. (2015) reported the clinical features of 2 unrelated females with MRD23, one of whom had previously been reported by Rauch et al. (2012). Both patients had delayed psychomotor development and delayed speech acquisition in infancy, although both later had fluent speech. Common dysmorphic features included low anterior hairline, broad nasal bridge with bulbous tip, long philtrum, and downturned corners of the mouth. One patient had low-set ears, strabismus, and prominent finger joints, whereas the other had myopia, astigmatism, and long, thin fingers.

Molecular Genetics

In 7 unrelated boys with moderate to severe intellectual disability, Grozeva et al. (2014) identified 7 different de novo heterozygous truncating or frameshift mutations in the SETD5 gene (see, e.g., 615743.0001-615743.0005), consistent with a loss of function and haploinsufficiency. The patients were ascertained from a larger cohort of 996 individuals with intellectual disability who were screened for mutations in 565 known or candidate genes using a targeted next-generation sequencing approach. All of the mutations were confirmed by Sanger sequencing, and molecular evidence was compatible with de novo occurrence. The patients accounted for 0.7% of the cohort, suggesting that SETD5 mutations may be relatively common causes of intellectual disability.

In 2 unrelated females with MRD23, Kuechler et al. (2015) described 2 different de novo heterozygous truncating mutations in the SETD5 gene (615743.0006 and 615743.0007). One of the patients had previously been reported by Rauch et al. (2012); this patient was ascertained from a cohort of 51 patients with intellectual disability who underwent exome sequencing. The patient reported by Kuechler et al. (2015) was part of a larger cohort of 250 individuals with developmental delay who underwent whole-exome sequencing. The findings were consistent with haploinsufficiency as the disease mechanism. Both patients accounted for 0.7% of the entire cohort.