Pathogenic genetic variants identified in Australian families with paediatric cataract

Abstract

Objective: Paediatric (childhood or congenital) cataract is an opacification of the normally clear lens of the eye and has a genetic basis in at least 18% of cases in Australia. This study aimed to replicate clinical gene screening to identify variants likely to be causative of disease in an Australian patient cohort.

Methods and analysis: Sixty-three reported isolated cataract genes were screened for rare coding variants in 37 Australian families using genome sequencing.

Results: Disease-causing variants were confirmed in eight families with variant classification as 'likely pathogenic'. This included novel variants PITX3 p.(Ter303LeuextTer100), BFSP1 p.(Glu375GlyfsTer2), and GJA8 p.(Pro189Ser), as well as, previously described variants identified in genes GJA3, GJA8, CRYAA, BFSP1, PITX3, COL4A1 and HSF4. Additionally, eight variants of uncertain significance with evidence towards pathogenicity were identified in genes: GJA3, GJA8, LEMD2, PRX, CRYBB1, BFSP2, and MIP.

Conclusion: These findings expand the genotype-phenotype correlations of both pathogenic and benign variation in cataract-associated genes. They further emphasise the need to develop additional evidence such as functional assays and variant classification criteria specific to paediatric cataract genes to improve interpretation of variants and molecular diagnosis in patients.

Keywords: Child health (paediatrics); Experimental & laboratory; Genetics; Lens and zonules.

Figure 1

Families with likely pathogenic variants in isolated paediatric cataract causing genes. (A) Family CRCH21 with a segregating previously described GJA3 p.(Pro59Leu) variant. (B) Family CRCH90 with a previously described GJA3 p.(Thr19Met) variant. (C) Family CRCH29 with a previously described CRYAA p.(Arg12Cys) variant. (D) Family CRCH38 with previously described COL4A1 p.(Gly720Asp) variant and MIR184 n.52T>C variant of uncertain significance. (E) Family CSA168 with previously described HSF4 p.(Lys64Glu) variant in the proband. (F) Family CRCH28 with a novel segregating PITX3 p.(Ter303LeuextTer100) variant and non-segregating EYA1 p.(Ser487Leu) variant. (G) Family CSA182 with a novel BFSP1 c.1124delA frameshift variant. (H) Family CRVEEH77 with a novel segregating GJA8 p.(Pro189Ser) variant altering an amino acid that has been previously associated with paediatric cataract.

Figure 2

Cataract phenotypes. (A) Lamellar cataract observed in CSA168-01 via slit-lamp photography using direct illumination. (B) Transillumination of CSA182-06, displaying the posterior sutural cataract phenotype with a pulverulent appearance was consistently observed in all affected individuals in the family.

Figure 3

Families with variants of uncertain significance that have evidence towards pathogenicity. Families with gap junction variants include: (A) GJA8 p.(Gly22Ser) in family CRCH137, (B) GJA8 p.(Lys131del) in family CTAS71 shown in ‘R’ for sequencing with reverse primer, and (C) GJA3 p.(Gln15Lys) in family CSA192. Five families were observed to have variants of uncertain significance in other cataract associated genes. (D) family CRVEEH79 with a start loss variant in the LEMD2 gene. (E) Family CSA93 with a segregating PRX p.(Arg129His) change. (F) Family CTAS34 with a segregating CRYBB1 p.(Ile94Asn) variant and MIP variant was also observed but also present in an unaffected individual. (G) family CQLD130 with a BFSP2 p.(Arg89Trp) variant that is also observed in unaffected CQLD130-04 and is acting with possible reduced penetrance. (H) In family CRCH4 a MIP p.(Arg113Gln) variant was observed in the two affected individuals and obligate heterozygote CRCH4-03, as well as, unaffected siblings CRCH4-06 and CRCH4-08.