Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.
We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Melissa B
MB
Ramocki
Magdalena
M
Bartnik
Przemyslaw
P
Szafranski
Katarzyna E
KE
Kołodziejska
Zhilian
Z
Xia
Jaclyn
J
Bravo
G Steve
GS
Miller
Diana L
DL
Rodriguez
Charles A
CA
Williams
Patricia I
PI
Bader
Elżbieta
E
Szczepanik
Tomasz
T
Mazurczak
Dorota
D
Antczak-Marach
James G
JG
Coldwell
Cigdem I
CI
Akman
Karen
K
McAlmon
Melinda P
MP
Cohen
James
J
McGrath
Elizabeth
E
Roeder
Jennifer
J
Mueller
Sung-Hae L
SH
Kang
Carlos A
CA
Bacino
Ankita
A
Patel
Ewa
E
Bocian
Chad A
CA
Shaw
Sau Wai
SW
Cheung
Tadeusz
T
Mazurczak
Paweł
P
Stankiewicz
D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data
D004268:DNA-Binding Proteins; C073368:HIP1 protein, human