Cataract 46, Juvenile-Onset

A number sign (#) is used with this entry because of evidence that juvenile-onset cataract-46 (CRCT46) is caused by homozygous mutation in the LEMD2 gene (616312) on chromosome 6p21.

Clinical Features

Shokeir and Lowry (1985) found 9 cases in 4 sibships of an inbred Lehrerleut Hutterite group. Apart from the cataracts, all were healthy, with normal growth and development. Specifically, no metabolic disorder could be identified. Intelligence, hearing, and behavior were normal. The patients were neurologically intact. There were no ocular lesions other than the cataracts.

Boone et al. (2016) reported 4 Lehrerleut Hutterite kindreds with juvenile cataract, including sibships previously studied by Shokeir and Lowry (1985) and Gerull et al. (2013). Age of cataract presentation was mostly between 3 and 7 years, although 1 individual presented at age 26. All pedigrees were consistent with autosomal recessive inheritance. In 2 of the pedigrees, 7 individuals died of sudden, apparently arrythmogenic events in the third through fifth decades; 6 of those patients also had juvenile-onset cataracts. Postmortem examination of 1 patient with juvenile cataracts showed myocardial scarring and fibrosis of the left lateral ventricular free wall, in the setting of normally distributed coronary arteries and no detectable coronary thrombi or vascular lesions.

Forsius et al. (1992) found 15 cases of juvenile cataract on the Aland Islands, which have about 23,000 inhabitants. Twelve of the cases belonged to 7 sibships of 2 different pedigrees and 3 cases were apparently sporadic; there were no genealogic connections in the last 6 to 10 generations to the 2 cataract pedigrees. One of the sporadic cases presented with a corrected cleft palate and a chromosomal anomaly. In another sporadic case, the mother probably had been infected with rubella during early gestation. In the third sporadic case, the cataract was combined with partial aniridia, but the patient had several genealogic connections to one of the cataract pedigrees. Parental consanguinity was detected in 5 of the 7 sibships, in some on multiple ancestral levels. Apart from the cataracts, all patients were healthy, with normal intelligence, behavior, hearing, growth, and development.

Mapping

Using exome data from 3 individuals with juvenile cataracts from 2 consanguineous Lehrerleut Hutterite kindreds and their parents, Boone et al. (2016) performed genomewide autozygosity mapping and identified a 9.5-Mb autozygous region on chromosome 6p22.2-p21.31 that was shared by all 3 patients and absent from their healthy parents. SNP-based fine mapping narrowed the critical interval to a subregion of 0.5 to 2.9 Mb (6p21.32-p21.31).

Molecular Genetics

In 17 affected members of 4 Lehrerleut Hutterite kindreds segregating autosomal recessive juvenile cataract mapping to 6p21.32-p21.31, Boone et al. (2016) identified homozygosity for a missense mutation in the LEMD2 gene (T38G; 616312) that segregated with cataract in all 4 families and was not found in public variant databases. In 2 of the kindreds, 6 patients with juvenile cataract also experienced sudden cardiac death (SCD). In 'sibship 2' from 1 of the kindreds (AR-900), previously studied by Gerull et al. (2013) as 'family L,' homozygosity for a nonsense mutation in the DSC2 gene (Q554X; 125645.0005) had been identified in an individual who experienced SCD. However, the Q554X variant was absent in an individual with cataract from another sibship from the same Hutterite kindred who experienced SCD, and was not present in the obligate carrier parents of the 5 other cataract patients who had SCD. Boone et al. (2016) concluded that the Q554X DSC2 variant did not explain SCD in their Hutterite families, other than in the previously studied sibship 2. Noting that variable age of onset and reduced penetrance are characteristic of inherited cardiomyopathies, the authors suggested that juvenile cataracts and sudden death might both be caused by mutation in the LEMD2 gene.

History

Saebo (1949) studied 17 families with cases of congenital or juvenile cataracts. Two or more sibs were affected in 8 families. In 9 families the parents were related, being first cousins in 5. In 1 family the proband had retinitis pigmentosa (268000), of which cataract is a known complication. In another family the proband had retinitis pigmentosa and congenital deafness (Usher syndrome, 276900). Recessively inherited congenital cataract was found to be frequent in Cyprus by Merin et al. (1972).