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Ophthalmology. 2014 Aug;121(8):1620-7. doi: 10.1016/j.ophtha.2014.02.008. Epub 2014 Mar 31.

Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration.

Author information

1
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
2
Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
3
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
4
Department of Ophthalmology, Fundación Jiménez Díaz, Madrid, Spain.
5
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
6
Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain.
7
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands.
8
Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
9
Department of Genetics, Insular-Materno Infantil University Hospital, Las Palmas de Gran Canaria, Spain.
10
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
11
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.
12
Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain. Electronic address: cayuso@fjd.es.

Erratum in

Abstract

OBJECTIVE:

To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype.

DESIGN:

Case series.

PARTICIPANTS:

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.

MAIN OUTCOME MEASURES:

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.

PMID:
24697911
DOI:
10.1016/j.ophtha.2014.02.008
[Indexed for MEDLINE]

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