Mental Retardation, Autosomal Dominant 57

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-57 (MRD57) is caused by heterozygous mutation in the TLK2 gene (608439) on chromosome 17q23.

Description

MRD57 is an autosomal dominant neurodevelopmental disorder with a highly variable phenotype. Most affected individuals have delayed psychomotor development apparent in infancy or early childhood, language delay, and behavioral abnormalities. Additional features may include hypotonia, feeding problems, gastrointestinal issues, and dysmorphic facial features (summary by Reijnders et al., 2018).

Clinical Features

Lelieveld et al. (2016) reported 2 patients with MRD57 associated with de novo heterozygous variants in the TLK2 gene. The patients were ascertained from a cohort of 820 parent-child trios with intellectual disability. A 20-year-old man (patient 17), born of consanguineous Turkish parents, had delayed psychomotor development with language delay and behavioral abnormalities, including tantrums and periods of hyperventilation. Additional features included myopia, strabismus, and diarrhea. Dysmorphic features included short forehead, upslanting palpebral fissures, epicanthal folds, hypertelorism, ptosis, flat midface, thin upper lip, and pointed chin. He also had kyphosis, scoliosis, and finger contractures. The second patient (patient 439) was a 7.5-year-old boy, born of unrelated Dutch parents, with feeding difficulties as a neonate followed by delayed motor, cognitive, and language development with a hoarse voice. He had difficulty regulating emotions and had anxiety. Other features included constipation, short stature, brachydactyly, and dysmorphic features, including upslanting palpebral fissures, blepharophimosis, ptosis, full nasal tip, and pointed chin.

Reijnders et al. (2018) reported 38 unrelated individuals and 2 affected mothers with a neurodevelopmental disorder associated with heterozygous variants in the TLK2 gene. Five of the patients had previously been reported by Lelieveld et al. (2016). The majority of the patients had delayed development with motor and language delay and were examined in childhood. Most (72%) had intellectual disability (IQ less than 70), 14% had borderline intellectual disability (IQ 70-85), and 6% had normal IQ (85 to 100). There was a broad range of behavioral abnormalities (present in 68% overall), including autism spectrum disorder, attention deficit-hyperactivity disorder, anxiety, obsessive-compulsive disorder, and social or emotional problems. Neurologic problems included hypotonia (37%), epilepsy (13%), and nonspecific intracranial brain abnormalities (13%). Skeletal abnormalities were observed in some patients, including joint hypermobility (21%), pes planus (21%), toe walking (18%), scoliosis (8%), and hand contractures (8%). Abnormalities of skull shape were seen in 31% of probands, including craniosynostosis in 4 patients. Common dysmorphic features included blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Less common dysmorphic features included pointed and tall chin (42%), epicanthal folds (42%), narrow mouth (32%), high palate (30%), microtia, first degree (29%), posteriorly rotated ears (29%), long face (27%), ptosis (21%), strabismus (26%), asymmetric face (16%), and hypertrichosis (16%). Short stature (37%) and microcephaly (24%) were also observed. Additional features included neonatal feeding difficulties (42%), constipation (55%), diarrhea (8%), recurrent otitis media (24%), eye refraction abnormalities (29%), and hoarse voice (8%).

Inheritance

The transmission pattern of MRD57 in 2 of the families reported by Reijnders et al. (2018) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 2 unrelated patients with MRD57, Lelieveld et al. (2016) identified de novo heterozygous mutations in the TLK2 gene (608439.0001 and 608439.0002). The patients were part of a cohort of 820 parent-child trios with intellectual disability who underwent exome sequencing. Functional studies of the variants were not performed, but the mutations were predicted to result in a loss of function and haploinsufficiency. Subsequent addition of data from 4 large previously published family-based sequencing studies identified 3 additional patients with TLK2 mutations. The entire cohort contained 2,104 family trios.

In 38 patients and 2 of their mothers with MRD57, Reijnders et al. (2018) identified heterozygous mutations in the TLK2 gene (see, e.g., 608439.0001-608439.0006). Five of the patients had previously been reported by Lelieveld et al. (2016). The vast majority of the mutations reported by Reijnders et al. (2018) occurred de novo, but there were 2 families in which the proband inherited a mutation from an affected mothers. Mutation types included 4 frameshift variants, 10 nonsense variants, 12 splice-site variants, and 9 missense variants. One patient carried a de novo balanced translocation. The mutations occurred throughout the gene. The authors performed RNA analysis of cells derived from 3 patients, which demonstrated that 2 of the mutations were subject to nonsense-mediated mRNA decay (NMD), resulting in haploinsufficiency; the third mutation was a nonsense mutation that escaped NMD, but was predicted to result in a truncated protein and haploinsufficiency. The mutations were found by whole-exome or whole-genome sequencing, and the patients and data were collected from 26 different research institutions in 7 different countries by means of data sharing by collaborators and matchmaker databases. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of patients with loss-of-function variants overlapped with phenotypes of individuals with missense and C-terminal truncated mutations, suggesting that that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype.