Mental Retardation, Autosomal Dominant 33

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-33 (MRD33) is caused by heterozygous deletion or mutation in the DPP6 gene (126141) on chromosome 7q36.

Clinical Features

Liao et al. (2013) reported a family with 4 affected members in 3 generations segregating autosomal dominant mental retardation. All 4 affected individuals had microcephaly (greater than -3 SD): a 56-year-old male with a head circumference of 51 cm, a 26-year-old female with a head circumference of 50 cm, a 29-year-old female with a head circumference of 50 cm, and a 5-year-old girl with a head circumference of 44 cm. One woman and her 5-year-old daughter were both small and thin (stature and weight -2 to -3 SD in both); an affected aunt had normal stature, and the grandfather had short stature, with a height of 163 cm. The proband had severe mental retardation and hyperactivity. The mother had microcephaly and mild mental retardation with an IQ of 65. The aunt had severe mental retardation and memory problems. The grandfather had mild mental retardation, with an IQ of 66.

Cytogenetics

Liao et al. (2013) reported 2 patients with microcephaly and mental retardation who had approximately 300-kb partially overlapping deletions in the DPP6 gene. The first patient (BY0712; 126141.0003), with a 336-kb deletion, was a 12-year-old boy with a head circumference of 47 cm (greater than -3SD), short stature, low body weight, and moderate mental retardation. He had attention deficit disorder and could only speak single words with ambiguous pronunciation. Skeletal radiographs showed delayed bone age. The second patient (BY2018), with a 362-kb deletion, was a 15-year-old girl with a head circumference of 48 cm (greater than -3SD), short stature, low body weight, and moderate mental retardation. She could only speak single words, and she had scoliosis and congenital amblyopia resulting from chorioretinal degeneration.

Molecular Genetics

Liao et al. (2013) conducted a copy number variation analysis of the DPP6 gene in patients with autosomal dominant microcephaly and variable mental retardation. The analysis was performed on DNA samples from 22 patients with microcephaly using high-resolution, array-based genomic hybridization. Two patients with small de novo deletions in the DPP6 gene were identified (see CYTOGENETICS). Sequence analysis was performed in another 50 microcephalic patients. A missense mutation in the DPP6 gene (M385L; 126141.0002) was identified in a family segregating microcephaly and autosomal dominant mental retardation. In mice, knockdown of Dpp6 using short hairpin RNA (shRNA) resulted in smaller brains and learning disabilities compared to wildtype littermates.