Mental Retardation, Autosomal Recessive 65

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-65 (MRT65) is caused by homozygous or compound heterozygous mutation in the KDM5B gene (605393) on chromosome 1q32.

Clinical Features

Faundes et al. (2018) reported 3 unrelated boys, aged 10, 11, and 18 years, with moderate to severe developmental delay and intellectual disability. Two were noted to have neonatal feeding difficulties and all had mild poor overall growth. The patients achieved walking and speech between 2 and 4 years of age; at least 1 was in mainstream school with learning difficulties at age 11. Two patients were noted to have variable dysmorphic facial features, including square face, downslanting palpebral fissures, ptosis, prominent metopic ridge, high nasal bridge with bulbous nasal tip, smooth philtrum, low-hanging columella, thin lips, and dysmorphic ears, as well as myopia, astigmatism, and strabismus. One patient had an atrial septal defect, cryptorchidism, and hypospadias, another had dolichocephaly and supernumerary nipple, and a third had inguinal hernia. Two had camptodactyly of the fourth and fifth fingers. Brain imaging in 1 patient showed a thin corpus callosum. None had seizures.

Martin et al. (2018) reported a 7-year-old boy (Decipher ID 259532) with developmental delay and specific learning disability, attention deficit disorder, sleep disturbance, and generalized joint laxity. He had macrocephaly at birth but normal brain imaging.

Inheritance

The transmission pattern of MRT65 in the families reported by Faundes et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 unrelated patients with MRT65, Faundes et al. (2018) identified homozygous or compound heterozygous mutations in the KDM5B gene (605393.0001-605393.0004). The first patient was ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing. The other 2 patients were identified from a cohort of 5,332 additional individuals from the DDD study who underwent exome sequencing. Segregation of the variants with the disorder was demonstrated only in 1 family. The KDM5B gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variants were filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project. Functional studies of the variants and studies of patient cells were not performed, but all mutations were nonsense or frameshift and were predicted to result in a loss of function.

Martin et al. (2018) reported a patient (Decipher ID 259532) with MRT65 who was a compound heterozygote for mutations in KDM5B, a large intragenic deletion encompassing exons 5 through 14 and a splice site mutation.

Heterozygous Mutations

Martin et al. (2018) reported 9 patients (6 males and 3 females) from the DDD study with de novo heterozygous mutations in the KDM5B gene. Six were loss of function and 3 were missense mutations. Patients ranged in age from 1.5 to 9 years. All had moderate developmental delay. There were no consistent dysmorphic features, and growth was normal in all the patients. Five of the patients had MRI, of which 3 were reported normal, 1 was reported abnormal, and 1 had cerebellar vermis hypoplasia and delayed myelination. Martin et al. (2018) also reported 22 heterozygous loss-of-function mutations in the KDM5B gene that were transmitted from parents. The authors stated that KDM5B is a recessive developmental disability gene in which heterozygous loss-of-function variants are incompletely penetrant.

Animal Model

Albert et al. (2013) found that homozygous deletion of Jarid1b (Kdm5b) in mice resulted in major neonatal lethality due to respiratory failure. Jarid1b-null embryos had neural defects, including disorganized cranial nerves, defects in eye development, and increased incidence of exencephaly and skeletal anomalies. Genomewide analysis of histone modification showed increased levels of H3K4me3 in Jarid1b knockout embryos during development, which resulted in abnormal expression of certain genes.

Martin et al. (2018) created a loss-of-function mouse model for KDM5B. Heterozygotes were normal and fertile. Homozygous KDM5B null mice were subviable (44% of expected). There was a fully penetrant vertebral patterning defect and numerous behavioral abnormalities including increased anxiety, less sociability, and reduced long-term memory compared with wildtype littermates.