Correlation between novel compound heterozygous ADAMTSL4 variants and primary phenotypes of ectopia lentis et pupillae

Purpose: To investigate molecular pathogenesis of congenital ectopia lentis accompanied by various ophthalmic manifestations. Methods: Three female siblings, their spouse and offspring underwent ophthalmic and general medical examinations. Genetic variants were screened with whole exome sequencing and analyzed in either dominant or recessive inheritance manner. Gene mutations were ascertained with the Sanger sequencing after polymerase chain reaction. Results: All three female siblings were diagnosed as the Ectopia lentis et pupillae (ELeP) through combination of clinical examination and genetic analysis. No characteristic pathological changes of skeletal, metabolic and cardiac abnormalities were observed. Novel compound heterozygous mutations (p.Ser264LeufsX37/ p.Gly757ValfsX62) in ADAMTSL4 were discreetly identified in this ELeP pedigree. The skin problem of three patients was recalled, and current symptom of the proband was observed further when we re-investigated after we identified the relevant variants. The molecular etiology of skin problem of three female siblings might be due to variants including ALOX15B, TRBV3-1, and NUDT18. Conclusions: Novel compound heterozygous ADAMTSL4 variants are responsible for ELeP in autosomal recessive inheritance manner in the current pedigree. Correlation between ADAMTSL4 variants and ELeP was firstly established based on our 12 years follow-up studies and previous reports of ELeP and ADAMTSL4–related eye disorders. The primary phenotypes caused by ADAMTSL4 variants include EL, EP, poor pupillary dilation, and axial elongation. Varying phenotypes including glaucoma, high myopia retinapathy, and poor vision and so on, may be secondary impairments. All these secondary impairments may be improved if proper clinical interventions are implemented in time