Chromosome 7q11.23 Deletion Syndrome, Distal, 1.2-Mb

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome on chromosome 7q11.23 (chr7:75.07-76.25 Mb, GRCh37) distal to the critical region for the Williams-Beuren syndrome (WBS; 194050).

Description

Hemizygous 1.2-Mb deletion of the distal region of chromosome 7q11.23 is associated with increased risk for epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities (Ramocki et al., 2010).

Clinical Features

Ramocki et al. (2010) identified 26 individuals from 10 unrelated families with variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities associated with hemizygous genomic deletions of distal chromosome 7q11.23. Epilepsy was common among deletion carriers, found in 8 (80%) of probands and 13 (50%) of all 26 family members. The intellectual spectrum was broad: of 12 surviving children, 7 (58%) had moderate to severe global developmental delay and/or were on the autistic spectrum, 2 (17%) had mild intellectual disability, 2 (17%) had learning disabilities, and only 1 (8%) was developmentally normal. Of 12 adult deletion carriers, 3 (25%) had mild intellectual disability, and 3 (25%) reported difficulties in school. However, 6 (50%) adults with deletions reported no cognitive difficulties, no special needs in the educational system, and no history of neuropsychiatric disease, indicating reduced penetrance. Behavioral problems were common among children, and included inattention, hyperactivity, impulsivity, and aggression.

Molecular Genetics

Ramocki et al. (2010) found distal chromosome 7q11.23 deletions that mapped between the WBS critical region and the MAGI2 gene (606382), ranging in size from 180 kb to 4 Mb, in 26 individuals from 10 unrelated families out of 29,510 individuals referred for chromosomal analysis. The distal 7q11.23 deletions were found at a frequency of 1 in 3,279 individuals referred for such problems. Six of the families and 1 isolated patient had a common recurrent 1.2-Mb deletion flanked by large complex low-copy repeats (75,071,539-75,071,906 to 76,256,141-76,256,508), likely mediated by nonallelic homologous recombination. The recurrent deletion spanned both the HIP1 (601767) and the YWHAG (605356) genes and was not found in 20,000 controls. Three patients had smaller deletions including only the HIP1 gene, and in the whole sample, deletion of the HIP1 gene was significantly associated with epilepsy (p = 2.224 x 10(-5)). In addition, Ramocki et al. (2010) found that 2 sibs with behavioral disorders had a reciprocal 1.2-Mb duplication of the same region, and a father and son with a spinal cord schwannoma and posterior encephalocele, respectively, had a smaller duplication including the HIP1 gene. None of the patients with a duplication had seizures. Ramocki et al. (2010) concluded that haploinsufficiency of the HIP1 gene may play a role in neurologic abnormalities.

Patients With Larger Deletions of Chromosome 7q11-q21

Marshall et al. (2008) found that the MAGI2 gene, which is telomeric to the WBS gene region, was hemizygously disrupted in 10 patients with a severe form of WBS that included infantile spasms and mental retardation. The disruption was part of a larger deletion, ranging in size from 5.5 to 19.6 Mb, at chromosome 7q11.23-q21.11 in all of these patients. In contrast, 9 WBS patients with deletions at 7q11.23 that did not disrupt the MAGI2 gene did not have infantile spasms. Marshall et al. (2008) also reported 5 patients without WBS but with infantile seizures, developmental delay, and other variable clinical features who had contiguous gene deletions in this region including the MAGI2 gene. The findings suggested that the MAGI2 gene may be a locus for infantile spasms and that its disruption may be responsible for infantile spasms in some WBS patients.

Marshall et al. (2008) found that 1 WBS patient with spasms did not have disruption of the MAGI2 gene: this was a Japanese male with a severe form of WBS associated with hypertrophic cardiomyopathy, craniosynostosis, and severe infantile seizures reported by Morimoto et al. (2003). FISH and high-resolution chromosome analysis revealed interstitial deletion of 7q11.22-q11.23, consistent with WBS syndrome. However, using high-resolution mapping, Marshall et al. (2008) found that the deletion in this patient was 4.4-Mb in length, extended telomeric to the classic WBS region, and included the YWHAG gene (605356).

Komoike et al. (2010) reported a Japanese girl with hypertrophic cardiomyopathy and severe infantile seizures who had the same deletion as the patient reported by Morimoto et al. (2003) and Marshall et al. (2008), although Komoike et al. (2010) reported that the size of the deletion was 4.1 Mb (72,338,350-76,475,408), including the YWHAG gene but not the MAGI2 gene. There was a region of duplicated segments at the telomeric breakpoint. Based on zebrafish models, Komoike et al. (2010) suggested that haploinsufficiency of the YWHAG gene was responsible for infantile spasms and cardiomegaly.

Rothlisberger et al. (2010) reported a 15-month-old girl with severe infantile seizures, hypsarrhythmia, and severe developmental delay. Array CGH analysis identified a heterozygous 13-Mb interstitial deletion of chromosome 7q11.21-q11.23 without involvement of the MAGI2 gene. Other features included ventricular and atrial septal defects, anal atresia, bilateral radioulnar synostosis, left inguinal hernia, and dysmorphic facies. The findings challenged the hypothesis that MAGI2 hemizygosity is responsible for infantile spasms.