Results of fibrillin-1 gene analysis in children from inbred families with lens subluxation.
BACKGROUND
Autosomal dominant mutation of the FBN1 gene (fibrillin-1) results in a spectrum of disease (type 1 fibrillopathies) ranging from Marfan syndrome with lens subluxation and cardiovascular complications to milder connective tissues phenotypes. The likelihood of FBN1 mutation in children referred to ophthalmologists because of lens subluxation is unclear. We report the results of routine FBN1 sequencing for children from inbred families referred with nontraumatic lens subluxation without cataract or vitreoretinal degeneration.


METHODS
Medical records of such patients from 2009 to 2012 were retrospectively reviewed.


RESULTS
Eight identified probands (3-11 years old; 4 boys) from consanguineous and/or endogamous Saudi Arabian families all harbored FBN1 mutation--7 autosomal dominant and 1 autosomal recessive (homozygous). Four mutations were novel. One child had a family history for lens subluxation. Seven had facial and/or skeletal features suggestive of type 1 fibrillinopathy. The parents of the autosomal recessive case were confirmed to be heterozygous carriers without lens subluxation or other clinical signs of type 1 fibrillinopathy.


CONCLUSIONS
Autosomal dominant type 1 fibrillinopathy was the major cause for lens subluxation in this cohort despite the fact that families were inbred and thus at higher risk for recessive disease. This highlights the frequency of new mutations in the gene and has important implications for genetic counseling and systemic assessment. The autosomal recessive case represents the fourth such case reported to date. Her heterozygous parents were unaffected carriers, suggesting that some FBN1 mutations can act as hypomorphic alleles rather than exhibiting the dominant negative effect typically attributed to FBN1 mutations.
Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. Electronic address: arif.khan@mssm.edu.
Arif O
AO
Khan
Center of Human Genetics, Bioscientia, Ingelheim, Germany; Institute of Human Genetics, University of Cologne, Cologne, Germany.
Hanno J
HJ
Bolz
Center of Human Genetics, Bioscientia, Ingelheim, Germany; Department of Nephrology & Center for Clinical Research, University Hospital Freiburg, Germany.
Carsten
C
Bergmann
D002135:Calcium-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007906:Lens Subluxation / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D012529:Saudi Arabia; D014792:Visual Acuity / Q000502:physiology; D054392:Adipokines
D002135:Calcium-Binding Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines