Mental Retardation, Autosomal Dominant 41

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-41 (MRD41) is caused by heterozygous mutation in the TBL1XR1 gene (608628) on chromosome 3q26.

Clinical Features

Saitsu et al. (2014) reported a 5-year-old Japanese girl with intellectual disability and autistic features. She developed infantile spasms at age 5 months. Electroencephalogram (EEG) later showed hypsarrhythmia and brain MRI revealed no structural brain anomalies; these features were consistent with a clinical diagnosis of West syndrome. She had no eye fixation or pursuit at age 7 months and had mild dysmorphic features. At age 8 months, she developed stereotypic hand movements; at age 5 years, she could walk with support, had a developmental quotient of 13, and showed autistic features.

Clinical Variability

Armour et al. (2009) reported a 15-year-old boy with global developmental delay, early-onset spastic paraparesis with increased lower limb muscle tone and bilateral extensor plantar responses, and dysfunctional bladder voiding with nocturnal enuresis. Physical examination at age 15 years showed microcephaly and small hands and feet with marked brachydactyly, particularly of the second and fifth fingers. Thumbs and big toes were short and broad, and radiographs showed short metacarpals and phalanges. He had a long oval face, facial asymmetry, small chin, dysarthria with hypernasal speech, and high-arched palate. One radiograph available from childhood showed cone-shaped epiphysis of the proximal phalanx of the right great toe. The patient also had Tourette syndrome (137580), which was also present in his otherwise unaffected brother. Karyotype and chromosomal microarray analyses were normal.

Cytogenetics

Tabet et al. (2014) reported a 6-year-old girl with nonspecific mild to moderate intellectual disability associated with a de novo heterozygous 1.6-Mb deletion on chromosome 3q26.31-q26.32 involving the TBL1XR1 gene and predicted to result in haploinsufficiency. Brain MRI and EEG were normal, and she did not have autistic features.

Pons et al. (2015) reported an 8-year-old girl and her mother who had the same 708-kb interstitial deletion on chromosome 3q26.32 encompassing only the TBL1XR1 gene; the deletion occurred de novo in the mother. Both individuals had mild to moderate intellectual disability, speech delay, and dysmorphic facial features, including synophrys, mild hypotelorism, depression of the nasal bridge, short nose with anteverted nares, long philtrum, pointed chin, low-set ears, and dental crowding. Clinodactyly and sandal gap were also noted. Autistic features were not present.

Molecular Genetics

In a 5-year-old Japanese girl with MRD41, Saitsu et al. (2014) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (G70D; 608628.0001). The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed.

In a girl with MRD41 and autistic features, O'Roak et al. (2012) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (L282P; 608628.0002). The patient had a nonverbal IQ of 47. Functional studies of the variant were not performed. The patient was from a cohort of 209 parent-child trios exhibiting sporadic autism spectrum disorders who underwent whole-exome sequencing. The same patient was also reported by O'Roak et al. (2012).

In a boy with MRD41 and autistic features, O'Roak et al. (2012) identified a de novo heterozygous truncating mutation in the TBL1XR1 gene (608628.0003). Functional studies of the variant were not performed. The patient was from a cohort of 2,446 autism spectrum disorder probands who underwent sequencing of 44 candidate genes.

In a patient with MRD41, Armour et al. (2016) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (Y245C; 608628.0004). The mutation was found by exome sequencing and confirmed by Sanger sequencing. The patient was originally reported by Armour et al. (2009) as having spastic paraparesis, brachydactyly, and dysmorphic facial features, but Armour et al. (2016) concluded that these additional features may not have been caused by the TBL1XR1 mutation. Functional studies of the variant were not performed.