A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder.
We studied a unique phenotype of cognitive delay, autistic behavior, and gait instability segregating in three separate sibships. We initiated genome-wide mapping in two sibships using Affymetrix 10K SNP Mapping Arrays and identified a homozygous 8.2 Mb region on chromosome 15 common to five affected children. We used exome sequencing of two affected children to assess coding sequence variants within the mapped interval. Four novel homozygous exome variants were shared between the two patients; however, only two variants localized to the mapped interval on chromosome 15. A third sibship in an Ohio Amish deme narrowed the mapped interval to 2.6 Mb and excluded one of the two novel homozygous exome variants. The remaining variant, a missense change in HERC2 (c.1781C>T, p.Pro594Leu), occurs in a highly conserved proline residue within an RCC1-like functional domain. Functional studies of truncated HERC2 in adherent retinal pigment epithelium cells suggest that the p.Pro594Leu variant induces protein aggregation and leads to decreased HERC2 abundance. The phenotypic correlation with the mouse Herc1 and Herc2 mutants as well as the phenotypic overlap with Angelman syndrome provide further evidence that pathogenic changes in HERC2 are associated with nonsyndromic intellectual disability, autism, and gait disturbance. Hum Mutat 33:1639-1646, 2012. © 2012 Wiley Periodicals, Inc.
Clinic for Special Children, Strasburg, PA 17579, USA. epuffenberger@clinicforspecialchildren.org
Erik G
EG
Puffenberger
Robert N
RN
Jinks
Heng
H
Wang
Baozhong
B
Xin
Christopher
C
Fiorentini
Eric A
EA
Sherman
Dominick
D
Degrazio
Calvin
C
Shaw
Carrie
C
Sougnez
Kristian
K
Cibulskis
Stacey
S
Gabriel
Richard I
RI
Kelley
D Holmes
DH
Morton
Kevin A
KA
Strauss
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002675:Child, Preschool; D002874:Chromosome Mapping; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D020233:Gait Disorders, Neurologic / Q000235:genetics; D056726:Genetic Association Studies; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D021381:Protein Transport; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases; D055815:Young Adult
D020662:Guanine Nucleotide Exchange Factors; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases