Behind the Blur: Early-Onset Bilateral Cataracts Genetic Test Program

No-cost genetic testing for 66 genes associated with early onset, often bilateral, cataracts is being offered for qualifying US-resident patients through a program sponsored by Mirum Pharmaceuticals. Individuals who meet eligibility criteria can receive a no-cost, genetic test, ordered by a qualified healthcare provider, to help determine if they have a genetic form of early onset cataracts.

Bilateral cataracts, defined as opacification of the crystalline lens of both eyes that results in abnormal refraction index and light scattering, are one of the most treatable causes of visual impairment during infancy. Cataracts account for one-tenth of the cases of childhood blindness (Francis and Moore 2004). Estimated prevalence rate is 1.2 - 6.0 per 10,000 live births. Early diagnosis and surgery and optical correction have resulted in an improved outcome for infants with either unilateral or bilateral cataracts (Lambert and Drack 1996).

Genetic testing may result in the diagnosis of a disorder that presents with isolated cataracts only or one that is syndromic, with cataracts as one of many possible clinical symptoms. Of particular interest is the early diagnosis of Cerebrotendinous Xanthomatosis (CTX), a rare, syndromic cause of early onset bilateral cataracts. CTX is an autosomal recessive genetic lipid storage and metabolic disorder caused by mutations in the CYP27A1 gene. Idiopathic, bilateral cataracts affect ~85% of patients with CTX, often with childhood onset. Early diagnosis of CTX can potentially lead to better patient outcomes.

Cataracts are most often inherited as an autosomal dominant trait, but also exhibit autosomal recessive or X-linked inheritance.

The genes in this panel are inherited in the following manner:

Autosomal dominant: BFSP2, CHMP4B, COL2A1, COL4A1, CRYBA1, CRYBA4, CRYBB2, CRYGC, CRYGS, DYNC1H1, EPHA2, FZD4, GJA3, GJA8, MIP, SLC16A12, TFAP2A, VIM, CRYGD, HSF4, MAF, MIR184, MYH9, NF2, UNC45B, BEST1, CRYBA2, NACC1, PAX6

Autosomal recessive: ABHD12, ADAMTSL4, ERCC2, FAM126A, FYCO1, GALE, LONP1, P3H2, RAB3GAP1, RECQL4, SC5D, SIL1, XYLT2, CYP27A1, GALK1, GALT, LEMD2, LIM2, WRN, RDH11, TGM3

Autosomal dominant OR recessive: ALDH18A1, COL11A1, COL18A1, FOXE3, GCNT2, OPA3, BFSP1, CRYAA, CRYAB, CRYBB1, FTL, PITX3

X-linked: BCOR, GLA, NDP, NHS

For this Next Generation Sequencing (NGS) test, sequencing is accomplished using exome capture probes (PGxome^®).

Copy number variants (CNVs) are also detected from NGS data. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Whole exome sequencing identified pathogenic variants in 9 probands from 23 pedigrees affected by familial dominant cataracts (39%) in several congenital or early-onset cataract genes (Reis et al. 2013). In another study of unselected cohort of 166 pediatric cataract patients from 74 families, candidate variants in cataract genes were identified in 58% (Patel et al. 2017). Mutation screening in 25 Chinese families with congenital or early-onset cataracts identified pathogenic variants in 10 families (40%) in 12 genes encoding crystallins and connexins. Approximately 32% of the families had pathogenic variants in crystallin genes and 8% of the families had pathogenic variants in connexin genes (Sun et al. 2011). Most genes referenced in these studies are included on this panel.

To our knowledge, no studies have indicated what percentage of the cataract population has copy number variants or which genes have a high frequency of deletion/duplications. Copy number variants in BFSP1, CRYAB, FAM126A, GCNT2, HSF4, NHS, PAX6, PITX3, and SIL1 have been reported to be causative to-date (Human Gene Mutation Database).

Patients must meet the criteria below:

• Patient age of 18 months to 35 years.
• Patient has current or history of idiopathic bilateral cataract(s) (e.g., not known to be due to infectious causes, trauma, etc.)
• Patient lives in the U.S.

Healthcare providers can request collection kits for the program by clicking the "Order Test Kits" button on this page.

Specimen Collection

WHOLE BLOOD

Collect 3 mL - 5 mL of whole blood in EDTA (purple top tube) or ACD (yellow top tube), minimum 1 mL for small infants.

SALIVA

Oragene^TM or GeneFiX^TM Saliva Collection kit used according to manufacturer instructions.

OCD-100 BUCCAL SWAB

OCD-100 Buccal Swab used according to manufacturer instructions.

DNA

Send in screw cap tube with at least 5 μg - 10 μg of purified DNA at a concentration of at least 100 ng/μL, minimum 2 μg for limited specimens. Label the tube with the composition of the solute and DNA concentration along with the patient's name, date of birth, and/or ID number. We only accept genomic DNA for testing; we do not accept products of whole genome amplification reactions or other amplification reactions. DNA must be extracted from a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by CAP and/or CMS.

Shipping and Handling Instructions

Label all specimen containers with the patient's name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.

WHOLE BLOOD

At room temperature or refrigerated, a blood specimen is stable for up to 8 days. Include a refrigerated gel pack in the shipping container. Fresh blood specimens are preferred. If frozen, a blood specimen is stable for up to 1 month before shipping. Frozen blood specimens should be shipped frozen (preferably on dry ice) overnight.

DNA, SALIVA, AND BUCCAL

At room temperature, an OCD-100 buccal specimen is stable for up to 80 days. Specimens of either type may be shipped at room temperature.