Ectopia lentis associated with a 20-base deletion in the ADAMTSL4 gene in the Old Order Amish population.

Background: ADAMTSL4-related eye disorder is a rare autosomal recessive disease with a wide spectrum of severity and expressivity. We describe the genotypic and phenotypic findings in a cohort of Ohio Anabaptist with a pathogenic ADAMTSL4 gene sequence variation.

Methods: Patient phenotypes were gathered from clinical data. Genetic information was collected using clinical exome sequencing followed by Sanger sequencing.

Results: Five patients from three Ohio Anabaptist families were determined to have a homozygous recessive ADAMTSL4 20-bp (c.767_786del) sequence variant. All five patients were found to have varying degrees of ectopia lentis and three patients presented with symptomatic lens subluxation. Average age of ectopia lentis diagnosis was 5 years (range 2-7 years). Additional features included persistent pupillary membrane and pupillary margin irregularities. The remaining two patients were asymptomatic and were found to have mild lens subluxation in adulthood, as they were examined following family genetic testing. Twenty-six heterozygous carriers were identified in a database of 1426 Ohio Old Order Amish individuals with an estimated carrier frequency of ~1:54 (allele frequency 0.91%).

Discussion: This is the first study to identify an ADAMTSL4 gene mutation in the Anabaptist population. Despite sharing the same genetic mutation, patients presented with a wide range of manifestations. A portion of affected individuals likely remain undiagnosed in the Anabaptist and general populations, especially if they are asymptomatic and only have mild lens subluxation. Implementation of early genetic screenings in high-risk populations can lead to improved awareness and patient outcomes.