The Use of Autozygosity Mapping and Next-Generation Sequencing in Understanding Anterior Segment Defects Caused by an Abnormal Development of the Lens

Abstract

The formation of the anterior segment of the eye is an intricate process that is dependent to a large degree on the normal development of the lens. Despite intensive study of the role of well-described eye genes, many causes of lenticular and anterior segment anomalies remain elusive. The majority of genes implicated thus far act in an autosomal dominant manner. Autosomal recessive causes are less well described; their diagnosis has been hindered by technological limitations, extreme genetic heterogeneity, a lack of understanding of eye biology and the role of many genes within the genome. The opportunity for the discovery of extremely rare autosomal recessive causes of ocular abnormalities from the study of consanguineous families is large, particularly through the powerful combination of next-generation sequencing with autozygosity mapping. Having begun to overcome the genetic heterogeneity bottleneck, it is increasingly recognised that the interpretation of genetic variants and the association of novel genes with a particular phenotype remain challenging. Nonetheless, increasing understanding of the genetic and mutational basis of lens and anterior segment abnormalities will be of enormous value to our comprehension of eye disease(s). Further, it will improve our ability to accurately interpret putative disease-causing variants with the aim of providing more personalised patient care and avoiding lifelong visual loss in children.

Emerging Trends and Research Foci in Cataract Genes: A Bibliometric and Visualized Study

“…These factors can lead to abnormal gene expression and affect the transparency of the lens, and eventually form cataract. Despite the in-depth study of eye's genes, It is still hard to find many causes that lead to abnormal lens (Gillespie et al, 2014 ). Hereditary cataract is a kind of clinical and genetic heterogeneity disease (Berry et al, 1999 ).…”

Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts

“…Abnormal development of the lens can cause ocular defects that include cataracts, glaucoma, microphthalmia, and anterior segment dysgenesis. 4,5 Infantile or early-childhood-onset cataracts-opacity that develops in the crystalline lens of the eye within the first year of life or before 5 years of age, respectively-is a major cause of visual impairment in children and is responsible for 5%-20% of visual impairment worldwide. 6 A recent systematic analysis has estimated the frequency of infantile cataracts as 4.2 cases per 10,000 children.…”

“…12 Autosomal-dominant, autosomal-recessive, and X-linked forms have been described, but a substantial fraction of genetic causes remain unknown. 5,13,14 Delineation of the precise underlying cause is important for clinical management 8 and is now possible with advanced sequencing technologies. 15 Recessive genetic disorders are more prevalent in consanguineous populations.…”

“…16 The genetic cause of lenticular abnormalities in children of consanguineous couples is mostly autosomal recessive; therefore, such families are of considerable importance for identifying candidate genes, understanding the biology of lens development, and elucidating the mechanisms of disease pathogencity. 5 By combining exome sequencing of one affected proband with homozygosity mapping and segregation analysis of family members, we have discovered candidate genes in families affected by suspected autosomal-recessive disorders. [17][18][19][20][21][22] Using this approach, we report three unrelated consanguineous Pakistani families (F372, F385, and F3) and 12 individuals who are affected by infantile-onset cataracts and harbor three different homozygous loss-of-function (LoF) variants in dynamin-binding protein (DNMBP [OMIM: 611282]).…”

Genetics of congenital cataract, its diagnosis and therapeutics

“…Congenital cataract is the type of cataract, which occurs at the early stages of life [2]. It is described as an opacity of the crystallin lens causing an impaired vision [3], and the abnormality of the lens can impede with the normal development of the eyes [4]. The prevalence varies with socioeconomic rank affecting 1-6 cases out of 10,000 live births in the developed countries and about 5-15 out of 10,000 cases in the developing countries of the world.…”