Genetic advances and impact on paediatric eyecare: focus on congenital cataract

Investigation of congenital cataract

Half of congenital cataracts are thought to be inherited, with non-genetic causes including intrauterine infection, trauma and developmental anomalies such as persistent foetal vasculature⁵. The inherited forms encompass not only isolated lens protein genes but metabolic genes, for instance GALAC1 associated with galactosemia and syndromic conditions such as trisomy 21 (Down syndrome, see Fig 2 and Fig 3).

Traditionally, the investigation of congenital cataract involved lengthy and expensive investigations including serum glucose, urinary-reducing substances and other biochemical and metabolic blood tests. However, the approach has changed in the last few years with the advent of accurate and fast NGS gene panels. These can solve up to 75% of bilateral congenital cataract and can be faster than traditional systemic investigations⁶. One study found traditional investigations yielded a diagnosis in only one of 27 patients with bilateral congenital cataract versus nine of 15 of the same patients undergoing next-generation sequencing testing⁷.

The latest high-throughput NGS technology permits the parallel sequencing of multiple genes with targeted regions (typically the protein-coding exonic regions plus known intronic variants) read multiple times to ensure accurate and thorough investigation. Complex bioinformatics help to interpret the resulting huge data and filter out likely pathogenic variants (mutations). Panels are flexible and can be updated as new genes are discovered. Identified variants can then be confirmed with Sanger polymerase chain reaction (PCR) sequencing, the gold standard traditional method of sequencing DNA. While the underlying cause of the cataract may be apparent from other ocular findings or known systemic diagnoses, such as trisomy 21, for the remainder, further investigations are warranted to understand systemic risks and the chance of further affected children. NGS gene panel testing of all known genes associated with ophthalmic disease is a broad, accurate and relatively fast approach for these patients⁶. Our practice in Auckland has changed in recent years to initiate this testing at the time of surgery for patients with suspected congenital cataract with a blood sample taken while under general anaesthesia for DNA extraction. The following two case examples demonstrate how this useful approach can benefit our patients.

Case 1

A 14-week-old baby failed a red reflex test at the GP and was urgently referred to the eye clinic. Bilateral, asymmetrical cataract was identified. There was no family history of cataract in childhood and no consanguinity. Surgery was delayed due to concurrent sickness. Left lens extraction and anterior vitrectomy were performed at 18 weeks of age with extended-wear contact lens introduced one week later. Blood tests at the time of surgery were sent for an NGS gene panel of 936 genes (Molecular Vision Lab (MVL) Vision Panel v7, Oregon, USA) with results available seven weeks later. This identified a mutation in CRYAA that was previously described in a family with autosomal dominant cataract⁸.

CRYAA encodes alpha-A crystallin, one of the major proteins that make up the lens. Mutations are thought to cause protein aggregation⁹. Examination of both parents and the older sibling found no cataract and segregation is underway to prove that this mutation was de novo. The genetic diagnosis provided reassurance that this was an isolated congenital cataract and further systemic investigation was not required.

Case 2

A five-week-old baby was referred to the ophthalmology service with recently noticed anisocoria. Bilateral, asymmetrical cataract were identified with relative right microphthalmia. There was no family history of congenital cataract. The patient was known to have congenital heart disease. Bilateral sequential lens extraction and anterior vitrectomy were performed under the same general anaesthetic at eight weeks of age with contact lens wear started one week later. MVL vision panel v10 (942 genes) was initiated with results available seven weeks later. This found a nonsense mutation in BCOR which encodes BCL6 corepressor that may influence apoptosis and is widely expressed throughout the body¹⁰. Mutations in females are associated with X-linked dominant BCOR-related syndrome that has variable systemic involvement including ocular, dental, hearing, skeletal, facial and cardiac. This molecular diagnosis enabled targeted systemic investigation for the patient and explained the congenital heart problems.

Conclusion

These cases illustrate how from one blood test, an accurate and relevant diagnosis was rapidly achieved. For those patients presenting with such a visually significant condition, this change in practice to pursue genetic diagnosis is of great benefit. In the majority of inherited cataracts, gene panel testing is expected to identify the underlying diagnosis.

References

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Dr Sarah Hull completed her medical training at the University of Cambridge and Imperial College, London, and her PhD in paediatric retinal genetics at UCL and Moorfields in 2016. Having completed her ophthalmology training in the UK, she undertook a paediatric fellowship in Auckland and now specialises in paediatrics, strabismus and genetics. She consults in Auckland and at Auckland Eye, and is a senior lecturer at Auckland University.