A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-68 (MRD68) is caused by heterozygous mutation in the KMT2B gene (606834) on chromosome 19q13.

Heterozygous mutation in the KMT2B gene can also cause childhood-onset dystonia-28 (DYT28; 617284).

Autosomal dominant intellectual developmental disorder-68 (MRD68) is characterized by developmental delay/intellectual disability, microcephaly, poor growth, feeding difficulties, and dysmorphic features. Some patients may have autism spectrum disorder or attention deficit-hyperactivity disorder (ADHD) (Cif et al., 2020).

Faundes et al. (2018) reported an 11-year-old girl with severe global developmental delay, poor growth, and microcephaly (-3.34 SD). She had delayed walking at age 6.5 years, poor speech, hand stereotypies, nystagmus, urinary incontinence, poor feeding requiring gastrostomy tube, and dysmorphic facial features such as sparse hair, large mouth, high palate, and absent ear lobes.

Cif et al. (2020) reported 9 patients (patients 45-53), who ranged from 2.2 to 57 years of age, with MRD68. The patients were ascertained through international collaborative efforts after genetic analysis identified heterozygous mutations in the KMT2B gene. Clinical features included developmental delay/intellectual disability, speech delay, microcephaly, growth delay, feeding problems, and dysmorphic features, including epicanthic folds, posteriorly rotated ears, syndactyly/clinodactyly of toes, and fifth finger clinodactyly. Brain MRI, performed in 5 patients, was normal. Several patients had autism or ADHD. None of the patients had dystonia.

The heterozygous mutation in the KMT2B gene that was identified in a patient with MRD68 by Faundes et al. (2018) occurred de novo.

The heterozygous mutations in the KMT2B gene that were identified in 7 of the 9 patients with MRD68 reported by Cif et al. (2020) occurred de novo. The transmission pattern in 1 case was consistent with autosomal dominant inheritance, although the mother (P46) had MRD68, and her son (P17) had DYT28, suggesting variable expressivity. The other MRD68 patient (P47) had the same mutation as a sib with DYT28 (P18), although the parents of these individuals were not studied.

In an 11-year-old girl with MRD68, Faundes et al. (2018) identified a de novo heterozygous 1-bp duplication in the KMT2B gene (c.1808dupC; 610881.0009). The patient was ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing. The KMT2B gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variant was filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project.

Cif et al. (2020) reported 9 patients (patients 45-53) with MRD68 associated with heterozygous mutations in the KMT2B gene that were identified by gene panel, whole-exome, or Sanger sequencing. There were 6 truncating mutations (see, e.g., 606834.0012) and 3 missense mutations. The protein-truncating mutations occurred throughout the gene, whereas missense variants clustered in putative functional domains. Functional studies of the variants were not performed, and the authors noted that missense variants should be interpreted with caution. It was postulated that haploinsufficiency or dysfunction of KMT2B affects the downstream expression of key genes regulating neurodevelopment and motor control. There were some instances of discordant phenotypes associated with a particular mutation that resulted in both DYT28 and MRD68 (see, e.g., 606834.0010 and 606834.0011). The finding of the same mutation in individuals with discordant phenotypes illustrated the phenotypic spectrum that can result from KMT2B mutations. The authors suggested that disease manifestations may be influenced by other genetic, epigenetic, or environmental factors.