Mental Retardation With Language Impairment And With Or Without Autistic Features

A number sign (#) is used with this entry because mental retardation with language impairment and with or without autistic features is caused by heterozygous mutation in the FOXP1 gene (605515) on chromosome 3p13.

Description

Mental retardation with language impairment and with or without autistic features is a neurodevelopmental disorder characterized by global developmental delay with moderate to severe speech delay that particularly affects expressive speech. Most patients have articulation defects, but frank verbal dyspraxia is not observed. Common dysmorphic features include broad forehead, downslanting palpebral fissures, short nose with broad tip, relative macrocephaly, frontal hair upsweep, and prominent digit pads. Gross motor skills are also delayed. Some patients have autistic features and/or behavioral problems. All reported cases have occurred de novo (review by Le Fevre et al., 2013).

Clinical Features

Hamdan et al. (2010) reported 2 unrelated children of French Canadian origin with a developmental disorder characterized by mild to moderate mental retardation, language impairment, and autistic features. Both showed global delay, delayed walking, and severely delayed speech development, with first words being spoken at age 3 and 6 years, respectively. Neither had evidence of an oromotor coordination defect. The first patient showed autistic features but did not meet full criteria due to some residual communication abilities, whereas the second patient met full criteria for autism (209850). Both patients showed severely limited expressive language, using single words or short sentences, although vocabulary was adequate in 1. Both showed better ability in receptive language comprehension. Both patients also showed behavioral abnormalities, including irritability, hyperactivity, aggression, and stereotypic rigid behaviors.

Horn et al. (2010) identified 3 unrelated children with moderate mental retardation (IQ less than 50) associated with de novo heterozygous intragenic deletions affecting only the FOXP1 gene. The patients were ascertained from a cohort of 1,523 German patients with mental retardation who underwent analysis for copy number variation. All 3 children had delayed psychomotor development and severely impaired speech and language development, particularly affecting expressive language. All also had dysgrammatism and poor speech articulation with difficulties pronouncing consonants, and 2 had oromotor problems with a tendency to hold the mouth open. Walking occurred between 2 and 3 years of age. Two patients had mild dysmorphic features, including prominent forehead and frontal hair upsweep. The deletions were of paternal origin in all patients. One of 4,104 controls was found to have a large 1.3-Mb deletion of chromosome 3p14.1-p13 encompassing the entire FOXP1 gene and 3 additional neighboring genes, suggesting the possibility of incomplete penetrance.

Le Fevre et al. (2013) reported a 6.5-year-old boy with mental retardation and significant language impairment. In infancy, he had failure to thrive associated with oromotor dysfunction and excessive drooling. He showed delayed psychomotor development, with walking at age 25 months and a notable delay in speech and language acquisition with articulation difficulties. He did not have autistic features or behavioral problems. Mild dysmorphic features, including large head, prominent forehead, downslanting palpebral fissures, flat malar region, and short nose with broad tip, were also noted.

Srivastava et al. (2014) reported a child with mental retardation with language impairment. Additional features in this patient included macrocephaly, delayed development, and delayed myelination on brain imaging.

Sollis et al. (2016) reported 3 unrelated children with a neurodevelopmental disorder characterized by global developmental delay, delayed walking, variable mental retardation, hypotonia, and speech-language impairment. One had articulation defects, another had apraxia of the tongue, and the third mostly lacked speech and had poor articulation. All had variable behavioral abnormalities, including obsessions and compulsions, stereotypical behavior, autistic features, attention deficit-hyperactivity disorder, and anxiety. Some patients had mild dysmorphic features, including macrocephaly, large forehead, hypertelorism, short nose, broad nasal tip, downslanting eyes, strabismus, and retrognathia. One patient had nystagmus and 2 had sensory integration disorder.

Cytogenetics

Carr et al. (2010) reported a boy with severe speech delay and delayed motor development who carried a de novo heterozygous 1.0-Mb interstitial deletion of chromosome 3p14.1 that involved only the FOXP1 gene. The phenotype was confounded by a Chiari I malformation, which was surgically corrected at age 30 months. The patient had delayed gross motor skills and walked at 16 months. After surgery for the Chiari malformation, he had some improvement in motor skills. The most significant feature was speech delay with limited verbal output and difficulty in articulating entire words and multisyllabic speech, although he did not have a deficit in oromotor coordination. At age 4 years, he developed staring spells with motor arrest associated with epileptiform discharges. He had mild dysmorphic facial features, including broad forehead, hypertelorism, downslanting palpebral fissures, ptosis, short nose, broad nasal tip, and smooth philtrum. Carr et al. (2010) concluded that FOXP1 may play a role in the development of verbal and motor skills.

Molecular Genetics

Hamdan et al. (2010) identified 2 different de novo heterozygous mutations in the FOXP1 gene (605515.0001 and 605515.0002, respectively) in 2 unrelated children of French Canadian origin with moderate mental retardation, expressive language deficits, and autism spectrum disorder (ASD). The first mutation (605515.0001) was a small deletion found using array-based comparative genomic hybridization of a cohort of 80 patients with ASD and 30 with intellectual disability. The second mutation (R525X; 605515.0002) was found by direct sequencing of the FOXP1 gene in a cohort of 110 patients with intellectual disability, 84 with ASD, and 51 with both. Hamdan et al. (2010) chose to examine the FOXP1 gene specifically because of the role of the FOXP2 gene (605317) in a speech and language disorder (SPCH1; 602081); patients with intellectual disability and ASD often show language impairment. The results indicated that disruption of FOXP1 has a global impact on brain development.

In a 6.5-year-old boy with mental retardation and significant language impairment, Le Fevre et al. (2013) identified a de novo heterozygous intragenic deletion in the FOXP1 gene (605515.0003) predicted to result in haploinsufficiency.

In a child with mental retardation with language impairment, Srivastava et al. (2014) identified a de novo missense mutation in the FOXP1 gene (W534R; 605515.0004). The patient was ascertained from a cohort of 78 patients with various neurodevelopmental disorders who underwent whole-exome sequencing.

In 3 unrelated patients with mental retardation and language impairment, Sollis et al. (2016) identified 3 different de novo heterozygous mutations in the FOXP1 gene (605515.0005-605515.0007). The mutations, including 1 nonsense and 2 missense mutations, were found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro studies showed that the mutations resulted in altered cellular localization and formation of protein aggregates, as well as loss of transcriptional repression activity. The variants retained the ability to interact with wildtype FOXP1, suggesting that they could exert a dominant-negative effect.