Mental Retardation, Autosomal Dominant 29

A number sign (#) is used with this entry because autosomal dominant mental retardation-29 (MRD29) is caused by heterozygous mutation in the SETBP1 gene (611060) on chromosome 18q12.

Clinical Features

Coe et al. (2014) reported 9 patients, including 1 reported by Rauch et al. (2012), with frameshift or nonsense mutations in SETBP1 who had a cognitive phenotype ranging from normal with impaired speech to profound intellectual disability (ID). The majority of patients had speech and motor delays, mild dysmorphic features, and behavioral difficulties. Two of the patients had seizures or EEG abnormalities. In addition, the authors reported 1 patient with a deletion encompassing the SETBP1 gene. Coe et al. (2014) also reported on 1 patient studied by Marseglia et al. (2012) and 2 patients studied by Filges et al. (2011). These patients had mild or moderate ID, speech and motor delays, and facial dysmorphisms. Two of the 3 patients had seizures or EEG abnormalities. In patients positive for mutation in SETBP1, Coe et al. (2014) observed a dysmorphism typified by a long face, characteristic eyebrows, and, in a few patients, low-set ears and cafe-au-lait spots. In 7 of 13 patients for whom brain MRI was available, no abnormalities were found; in 1 additional patient, MRI showed no major anomalies but minimal signal of the peritrigonal white matter.

Molecular Genetics

Coe et al. (2014) created an expanded copy number variant (CNV) morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. They then resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Among these was SETBP1, haploinsufficiency of which was associated with intellectual disability and loss of expressive language. Coe et al. (2014) reported 4 nonsense mutations in SETBP1 (e.g., 611060.0007), 2 of which were confirmed to be de novo, as well as 4 frameshift mutations (e.g., 611060.0006), of which 1 was confirmed to be de novo.