Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration.
OBJECTIVE
To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype.


METHODS
Case series.


METHODS
Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (RP) plus noncongenital and progressive hearing loss, ataxia, or both, respectively.


METHODS
A whole exome sequencing (WES) analysis was performed in 2 families segregating arRP. A mutational screening was performed in 378 additional unrelated families for the exon-intron boundaries of the ABHD12 gene. To establish a genotype-phenotype correlation, individuals who were homozygous or compound heterozygotes of mutations in ABHD12 underwent exhaustive clinical examinations by ophthalmologists, neurologists, and otologists.


METHODS
DNA sequence variants, best-corrected visual acuity, visual field assessments, electroretinogram responses, magnetic resonance imaging, and audiography.


RESULTS
After a WES analysis, we identified 4 new mutations (p.Arg107Glufs*8, p.Trp159*, p.Arg186Pro, and p.Thr202Ile) in ABHD12 in 2 families (RP-1292 and W08-1833) previously diagnosed with nonsyndromic arRP, which cosegregated with the disease among the family members. Another homozygous mutation (p.His372Gln) was detected in 1 affected individual (RP-1487) from a cohort of 378 unrelated arRP and syndromic RP patients. After exhaustive clinical examinations by neurologists and otologists, the 4 affected members of the RP-1292 had no polyneuropathy or ataxia, and the sensorineural hearing loss and cataract were attributed to age or the normal course of the RP, whereas the affected members of the families W08-1833 and RP-1487 showed clearly symptoms associated with polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract (PHARC) syndrome.


CONCLUSIONS
Null mutations in the ABHD12 gene lead to PHARC syndrome, a neurodegenerative disease including polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract. Our study allowed us to report 5 new mutations in ABHD12. This is the first time missense mutations have been described for this gene. Furthermore, these findings are expanding the spectrum of phenotypes associated with ABHD12 mutations ranging from PHARC syndrome to a nonsyndromic form of retinal degeneration.
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Koji M
KM
Nishiguchi
Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
Almudena
A
Avila-Fernandez
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
Ramon A C
RA
van Huet
Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
Marta
M
Corton
Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
Raquel
R
Pérez-Carro
Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
Esther
E
Martín-Garrido
Department of Ophthalmology, Fundación Jiménez Díaz, Madrid, Spain.
María Isabel
MI
López-Molina
Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
Fiona
F
Blanco-Kelly
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Lies H
LH
Hoefsloot
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Wendy A
WA
van Zelst-Stams
Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain.
Pedro J
PJ
García-Ruiz
Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain.
Javier
J
Del Val
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Silvio Alessandro
SA
Di Gioia
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands.
B Jeroen
BJ
Klevering
Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Bart P C
BP
van de Warrenburg
Department of Genetics, Insular-Materno Infantil University Hospital, Las Palmas de Gran Canaria, Spain.
Carlos
C
Vazquez
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Frans P M
FP
Cremers
Department of Ophthalmology, Fundación Jiménez Díaz, Madrid, Spain.
Blanca
B
García-Sandoval
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
Carel B
CB
Hoyng
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Rob W J
RW
Collin
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Carlo
C
Rivolta
Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain. Electronic address: cayuso@fjd.es.
Carmen
C
Ayuso
D000328:Adult; D000368:Aged; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D001299:Audiometry; D002386:Cataract / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D004596:Electroretinography; D059472:Exome / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008994:Monoacylglycerol Lipases / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011115:Polyneuropathies / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D017433:Protein Structure, Secondary; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D017422:Sequence Analysis, DNA; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology
C552558:ABHD12 protein, human; D008994:Monoacylglycerol Lipases