TY - JOUR
T1 - Pathogenic genetic variants identified in Australian families with paediatric cataract
AU - Jones, Johanna L.
AU - McComish, Bennet J.
AU - Staffieri, Sandra E.
AU - Souzeau, Emmanuelle
AU - Kearns, Lisa S.
AU - Elder, James E.
AU - Charlesworth, Jac C.
AU - Mackey, David A.
AU - Ruddle, Jonathan B.
AU - Taranath, Deepa
AU - Pater, John
AU - Casey, Theresa
AU - Craig, Jamie E.
AU - Burdon, Kathryn P.
PY - 2022/8/26
Y1 - 2022/8/26
N2 - 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 â € 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.
AB - 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 â € 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.
KW - Child health (paediatrics)
KW - Experimental & laboratory
KW - Genetics
KW - Lens and zonules
UR - http://www.scopus.com/inward/record.url?scp=85137886861&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1185477
UR - http://purl.org/au-research/grants/NHMRC/1116360
U2 - 10.1136/bmjophth-2022-001064
DO - 10.1136/bmjophth-2022-001064
M3 - Article
C2 - 36161833
AN - SCOPUS:85137886861
SN - 2397-3269
VL - 7
JO - BMJ Open Ophthalmology
JF - BMJ Open Ophthalmology
IS - 1
M1 - e001064
ER -