Mental Retardation, Autosomal Dominant 26

A number sign (#) is used with this entry because autosomal dominant mental retardation-26 (MRD26) is caused by heterozygous intragenic copy number variation in the KIAA0442 gene (AUTS2; 607270) on chromosome 7q11.

Clinical Features

Beunders et al. (2013) compared 17 well-characterized individuals with exonic deletions in AUTS2 and found a variable syndromic phenotype, including intellectual disability, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. Beunders et al. (2013) found that all 17 probands for whom clinical data were available had intellectual disability and/or developmental delay; this had been the reason for diagnostic testing. One of the parents carrying an AUTS2 deletion had learning difficulties, 1 had mild intellectual disability, and 1 had normal intelligence. Seven of the 17 probands were diagnosed with autism spectrum disorder or showed autistic behavior. Among the complete cohort of 21 individuals consisting of 17 probands and 4 family members carrying the AUTS2 deletion, 13 females and 8 males ranging in age from 11 months to 32 years at the time of examination, Beunders et al. (2013) observed low birthweight in 41% (7/17), short stature in 60% (12/20), microcephaly in 70% (14/20), and feeding difficulties in 48% (10/21). Only 14% (3/21) manifested hyperactivity disorder and/or ADHD. Thirty-eight percent (8/21) were hypotonic, 27% (3/11) had a structural brain anomaly, and 43% (9/21) had cerebral palsy and/or spasticity. Dysmorphic features noted by Beunders et al. (2013) included hypertelorism, ptosis, short and/or upturned philtrum, short palpebral fissures, prominent nasal tip, and narrow mouth. Skeletal abnormalities included kyphosis and/or scoliosis, arthrogryposis and/or shallow palmar creases, and tight heel cords. Beunders et al. (2013) developed an AUTS2 syndrome severity score. Cases and family members with 5-prime in-frame deletions scored significantly lower than did cases and family members with deletions of downstream exons, whole-gene deletions, or exon 1 through 4 deletions, including the initiation codon. This difference was significant, regardless of the inclusion or exclusion of affected family members, prompting further analysis of the 3-prime gene region of AUTS2.

Nagamani et al. (2013) reported 4 patients with copy number variations (CNVs) ranging in size from 133 to 319 kb that disrupted AUTS2. Two patients were sibs who inherited an identical 179-kb duplication of exon 5 from their mother. The other 2 patients had different intragenic deletions that involved exons 6 through 14. All patients had developmental delay. Both of the patients with the duplication had autism spectrum disorder. One had microcephaly, while the other was normocephalic; the normocephalic patient had seizures. The mother of these patients had microcephaly and mild intellectual disability. One deletion patient had macrocephaly, dysmorphic facial features, failure to thrive, scoliosis, and atrial septal defect; brain MRI was normal. Her 133-kb deletion arose de novo. The second deletion patient had a head circumference in the 11th percentile at 3 years of age. She had no features of autism or seizures, and brain MRI was normal. Her deletion, which was 319 kb, encompassed that of the other patient.

Beunders et al. (2015) reported 2 unrelated males in their twenties with MRD26. Both patients had delayed psychomotor development with intellectual disability, an autism spectrum disorder, feeding difficulties after birth, mild distal joint contractures, and mild dysmorphic features. Dysmorphic features included ptosis, prominent nasal tip, deep nasal bridge, and short or upturned philtrum. One patient had severely delayed speech and foot misalignment requiring surgery. The other also had short stature, highly arched eyebrows, short palpebral fissures, strabismus, low-set ears, microretrognathia, highly arched feet, and stiff movements with mild peripheral hypertonia. The clinical features, although slightly variable, were consistent with those reported previously in patients with MRD26.

Beunders et al. (2016) reported 13 patients, including 6 adults, with an intellectual disability syndrome caused by mutation in the AUTS2 gene. Three of the patients had previously been reported and were reevaluated. All patients had developmental delay and borderline to severe intellectual disability with poor speech. Most had microcephaly and feeding difficulties early in life due to hypotonia. Congenital malformations were rare, but mild heart defects, contractures, and genital malformations occurred occasionally. Motor development was slightly delayed, and many had hyperreflexia or hypertonia. Only 2 had seizures. Most individuals tended to have friendly, outgoing social interactions; some features of autism were often observed, but none were diagnosed with classic autism. Patients with a small in-frame 5-prime deletion, which was often inherited, had a milder phenotype compared to those with haploinsufficiency of the full-length AUTS2 transcript, which occurred de novo.

Molecular Genetics

By combining the results of diagnostic testing of 49,684 individuals, Beunders et al. (2013) identified 24 microdeletions that affected at least 1 exon of AUTS2, as well as 1 translocation and 1 inversion each with a breakpoint within the AUTS2 locus. The authors then analyzed 16,784 controls from 12 cohorts by using arrays with high-density coverage of the AUTS2 locus. Although 9 deletions were found, none of them disrupted an AUTS2 exon. The difference between exonic deletions in the cases (24 of 49,651) and those in controls (0 of 16,784) was highly significant (p = 0.00092), suggesting that exonic disruptions of AUTS2 give rise to a highly penetrant phenotype in humans. Dysmorphic features were more pronounced in persons with 3-prime AUTS2 deletions. This part of the gene encodes a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with their genetic data, Beunders et al. (2013) found that suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2.

In 2 unrelated men with MRD26, Beunders et al. (2015) identified 2 de novo heterozygous small deletions in the AUTS2 gene (607270.0003 and 607270.0004). Functional studies of the variants were not performed, but both were predicted to result in haploinsufficiency. The deletions were found by exome sequencing or array analysis.