Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy.
Inherited retinal dystrophies present extensive phenotypic and genetic heterogeneity, posing a challenge for patients' molecular and clinical diagnoses. In this study, we wanted to clinically characterize and investigate the molecular etiology of an atypical form of autosomal recessive retinal dystrophy in two consanguineous Spanish families. Affected members of the respective families exhibited an array of clinical features including reduced visual acuity, photophobia, defective color vision, reduced or absent ERG responses, macular atrophy and pigmentary deposits in the peripheral retina. Genetic investigation included autozygosity mapping coupled with exome sequencing in the first family, whereas autozygome-guided candidate gene screening was performed by means of Sanger DNA sequencing in the second family. Our approach revealed nucleotide changes in CDHR1; a homozygous missense variant (c.1720C>G, p.P574A) and a homozygous single base transition (c.1485+2T>C) affecting the canonical 5' splice site of intron 13, respectively. Both changes co-segregated with the disease and were absent among cohorts of unrelated control individuals. To date, only five mutations in CDHR1 have been identified, all resulting in premature stop codons leading to mRNA nonsense mediated decay. Our work reports two previously unidentified homozygous mutations in CDHR1 further expanding the mutational spectrum of this gene.
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Konstantinos
K
Nikopoulos
Department of Genetics, Instituto de Investigacion Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS - FJD, UAM), Madrid, Spain.|Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras ISCIII, Madrid, Spain.
Almudena
A
Avila-Fernandez
Department of Genetics, Instituto de Investigacion Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS - FJD, UAM), Madrid, Spain.|Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras ISCIII, Madrid, Spain.
Marta
M
Corton
Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras ISCIII, Madrid, Spain.|Department of Ophthalmology, University Hospital Fundacion Jimenez Diaz, Madrid, Spain.
Maria Isabel
MI
Lopez-Molina
Department of Genetics, Instituto de Investigacion Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS - FJD, UAM), Madrid, Spain.|Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras ISCIII, Madrid, Spain.
Raquel
R
Perez-Carro
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Lara
L
Bontadelli
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Silvio Alessandro
SA
Di Gioia
Department of Genetics, Instituto de Investigacion Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS - FJD, UAM), Madrid, Spain.|Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras ISCIII, Madrid, Spain.
Olga
O
Zurita
Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras ISCIII, Madrid, Spain.|Department of Ophthalmology, University Hospital Fundacion Jimenez Diaz, Madrid, Spain.
Blanca
B
Garcia-Sandoval
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Carlo
C
Rivolta
Department of Genetics, Instituto de Investigacion Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS - FJD, UAM), Madrid, Spain.|Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras ISCIII, Madrid, Spain.
Carmen
C
Ayuso
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D022821:RNA Splice Sites; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics*; D016415:Sequence Alignment; D013030:Spain; D044465:White People / Q000235:genetics
C442481:CDHR1 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D009419:Nerve Tissue Proteins; D022821:RNA Splice Sites