Mental Retardation, Autosomal Dominant 49

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-49 (MRD49) is caused by heterozygous mutation in the TRIP12 gene (604506) on chromosome 2q36.

Clinical Features

Bramswig et al. (2017) reported 11 unrelated patients with MRD49, including 4 patients who had previously been reported (see, e.g., Lelieveld et al., 2016 and Iossifov et al., 2014). The patients were of various ethnic origins, including European, Iranian, and Moroccan. They had delayed psychomotor development with delayed walking, mild intellectual disability, learning difficulties, and/or autistic features or behavioral abnormalities. Most had fluent speech, although several patients had delayed speech. Additional features included hypotonia (4 patients), seizures (3 patients), and strabismus (2 patients). A few had mild isolated dysmorphic facial features, such as hypertelorism, epicanthal folds, short nose, depressed nasal bridge, low columella, long philtrum, wide mouth, high-arched palate, and large ear lobes, and a few had mild abnormalities of the hands or feet, such as clinodactyly and sandal gap.

Zhang et al. (2017) reported 6 patients with MRD49, including 3 with intragenic deletions in the TRIP12 gene and 3 with point mutations resulting in truncated proteins. The patients had developmental delay with intellectual disability and poor or absent speech; 3 had autistic-like behavioral abnormalities. Two patients also had hyperactive or aggressive behavior. Dysmorphic features were highly variable and seen in only 1 or 2 patients, and included narrow and upslanting palpebral fissures, downturned corners of the mouth, wide mouth, hypertelorism, epicanthal folds, pointed chin, and large ear lobes. One patient had morbid obesity.

Molecular Genetics

In 2 unrelated patients with MRD49, Lelieveld et al. (2016) identified 2 different de novo heterozygous mutations in the TRIP12 gene. The patients were ascertained by analyzing whole-exome sequencing data on 2,104 parent-child trios in which the child had intellectual disability. Zhang et al. (2017) stated that both mutations identified by Lelieveld et al. (2016) resulted in truncated proteins.

In 11 patients with MRD49, Bramswig et al. (2017) identified heterozygous mutations in the TRIP12 gene (see, e.g., 604506.0001-604506.0003). The molecular findings of 4 of the patients (patients 4, 9, 10, and 11) had previously been reported (see, e.g., Lelieveld et al., 2016 and Iossifov et al., 2014). The mutations were identified by whole-exome sequencing from several different large patient cohorts, and all except 1 occurred de novo. Most of the mutations resulted in a truncated protein, although there were a few missense variants as well as a translocation. Functional studies of the variants were not performed, but Bramswig et al. (2017) speculated that haploinsufficiency was the major pathogenic mechanism. Of note, one of the patients (patient 6) inherited a missense variant (P5L) from his unaffected mother, and another patient (patient 8) carried a missense variant (A767V) that was later determined by Zhang et al. (2017) to be a variant of uncertain significance: Zhang et al. (2017) referred to the variant in patient 8 as A761V.

In 6 unrelated patients with MRD49, Zhang et al. (2017) identified heterozygous mutations involving the TRIP12 gene. Three patients (patients 6, 7, and 9) carried de novo point mutations resulting in truncated proteins (see, e.g., 604506.0004-604506.0006), whereas 3 patients (patients 1, 2, and 3) carried intragenic multiexon deletions. One of the intragenic deletions occurred de novo; parental DNA from the other 2 patients with intragenic deletions was not available. The mutations were predicted to result in haploinsufficiency, although functional studies and studies of patient cells were not performed. The findings suggested that TRIP12 plays an important role in nervous system development.