A genotype-phenotype comparison of ADAMTSL4 and FBN1 in isolated ectopia lentis.
OBJECTIVE
To describe the genotype-phenotype relationship of a cohort of consecutive patients with isolated ectopia lentis (EL) secondary to ADAMTSL4 and FBN1 mutations.


METHODS
Patients underwent detailed ocular, cardiovascular, and skeletal examination. This was correlated with Sanger sequencing of ADAMTSL4 and FBN1 genes.


RESULTS
Seventeen patients were examined, including one with ectopia lentis et pupillae. Echocardiography and skeletal examination revealed no sign of systemic disorders associated with EL, in particular Marfan syndrome (MFS). Nine patients (52.9%) were found to have mutations in ADAMTSL4, including four novel nonsense mutations. Four patients (25%) were found to have novel FBN1 mutations, not previously reported as causing classical Marfan syndrome. One additional patient was found to have an FBN1 mutation previously reported in classical MFS. Four patients (25%) were found to have no mutations in either gene. Median age of diagnosis of EL was 35 years in patients with FBN1 mutations and 2 years in patients with ADAMTSL4 mutations (P < 0.01). Mean axial length was 22.74 mm (95% confidence interval [CI]: 21.3-24.2) (FBN1) and 27.54 mm (95% CI: 24.2-30.9) (ADAMTSL4) (P < 0.01). Other ophthalmic features, including corneal thickness and power, foveal thickness, visual acuity, and direction of lens displacement, were similar for both groups.


CONCLUSIONS
ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.
Vitreoretinal Department, Moorfields Eye Hospital, City Road, London EC1V2PD, UK. aman.chandra@moorfields.nhs.uk
Aman
A
Chandra
Jose A
JA
Aragon-Martin
Kathryn
K
Hughes
Sabiha
S
Gati
M Ashwin
MA
Reddy
Charu
C
Deshpande
Graham
G
Cormack
Anne H
AH
Child
David G
DG
Charteris
Gavin
G
Arno
D000071096:ADAMTS Proteins; D000293:Adolescent; D000328:Adult; D000368:Aged; D000886:Anthropometry; D002648:Child; D015331:Cohort Studies; D004452:Echocardiography; D004479:Ectopia Lentis / Q000150:complications / Q000235:genetics*; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005838:Genotype; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000150:complications / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D019699:Thrombospondins / Q000235:genetics*; D055815:Young Adult; D054392:Adipokines
D000071096:ADAMTS Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D019699:Thrombospondins; C486779:ADAMTSL4 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines