Mental Retardation, Autosomal Dominant 39

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-39 (MRD39) is caused by heterozygous mutation in the MYT1L gene (613084) on chromosome 2p25.3. Some patients with a similar phenotype have deletions or duplications of chromosome 2p25.3 encompassing several genes, including MYT1L.

Clinical Features

De Rocker et al. (2015) described 2 unrelated patients with MRD39. Patient 14, originally reported by de Ligt et al. (2012), was a girl who presented with neonatal hypotonia and feeding difficulties soon after birth, and was noted to have developmental delay around 6 months of age. At age 12 years, she had an IQ of about 45 and showed autistic features. Mild dysmorphic features included broad base and bridge of the nose and a large mouth. Patient 15 was a 13-year-old boy with delayed development, especially affecting language, and autism spectrum disorder. At age 9 years, his IQ was about 50. He had brachycephaly and upwardly slanted narrow eyes.

Blanchet et al. (2017) reported 9 patients with MRD39. All had developmental delay or impaired intellectual development and gross motor delay. Most (85%) were overweight/obese and 70% had hyperphagia. CNS malformation and minor anomalies were each seen in 42% of patients. Autism and epilepsy were seen in 30% and 15% of patients, respectively. The proportions with impaired intellectual development, gross motor delay, speech delay, autism, overweight/obesity, and hyperphagia among patients with MYT1L haploinsufficiency were similar to those in patients with the 2p25.3 deletion syndrome, suggesting that MTY1L haplosufficiency is responsible for the 2p25.3 deletion phenotype.

Loid et al. (2018) reported a 13-year-old boy with MRD39 with early-onset obesity. The patient was overweight at age 1 year and obese at age 2 years. He had hyperphagia, speech delay, strabismus, hyperactivity, and neurologic, cognitive, and motor delay. The patient had no dysmorphic features, and his brain MRI was normal.

Cytogenetics

Stevens et al. (2011) identified heterozygous deletions of chromosome 2p25.3 in 3 adult sibs and 3 unrelated patients with intellectual disability. The patients were also overweight or obese but had no notable additional features. The deletions ranged in size from 0.37 to 3.13 Mb, and the minimal region of overlap included the MYT1L gene.

De Rocker et al. (2015) reported 14 patients, including 10 unrelated individuals and 4 members of the same family, with heterozygous deletions of chromosome 2p25.3 ranging in size from 120 kb to 6.07 Mb. All led to either partial or complete deletion of the MYT1L gene. Six additional patients, including 3 members of the same family, had 2p25.3 duplications ranging in size from 170 to 377 kb. These breakpoints were located in MYT1L, very likely leading to an aberrant transcript and loss of function. All patients, including the ones with duplications, had mild to moderate intellectual disability with speech delay, and the majority were overweight or obese. Additional features included behavioral problems, such as autism, aggression, hyperactivity, stereotypic hand movements, and sleep disturbances.

Mayo et al. (2015) reported a 4.5-year-old girl with a de novo intragenic deletion of MYT1L. She had neonatal hypotonia, microcephaly, delayed psychomotor development, and autistic features. Additional features included strabismus, myopia, recurrent otitis, and seizures; she was not overweight.

Inheritance

The transmission pattern of mental retardation in 2 families reported by De Rocker et al. (2015) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a 12-year-old girl with autosomal dominant mental retardation, de Ligt et al. (2012) identified a de novo splice site mutation in the MYT1L gene (613084.0001). The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. Functional studies of the variant were not performed.

In a 13-year-old boy with MRD39, De Rocker et al. (2015) identified a de novo heterozygous truncating mutation in the MYT1L gene (Y639X; 613084.0002).

Using trio exome sequencing and a Genematcher-facilitated collaboration, Blanchet et al. (2017) reported 9 patients with impaired intellectual development and obesity, consistent with MRD39, who had mutations in the MYT1L gene, including 4 loss-of-function and 5 missense (see, e.g., 613084.0003) mutations. Using a knockout cell line, MYT1L loss of function was shown to result in dysregulated expression of neurodevelopmental genes. A knockdown zebrafish model demonstrated loss of oxytocin expression in the preoptic neuroendocrine area, which might explain how MYT1L mutations result in obesity. MYT1L was shown to be expressed at significantly higher levels in the adult cerebral cortex than in the hippocampus, basal ganglia, and hypothalamus, and in multiple hypothalamic structures at 15 to 16 postconception weeks.

In a 13-year-old boy with MRD39 and early-onset obesity, Loid et al. (2018) identified a de novo heterozygous frameshift deletion in the MYT1L gene (613084.0004). The mutation was identified by whole-genome sequencing and confirmed by Sanger sequencing. The frameshift variant was not present in the 1000 Genomes Project, ExAC, SweGen, or SISu Project databases, but was found in 1 of 8,696 alleles in the African population in the gnomAD database.