Pathogenic variants of AIPL1, MERTK, GUCY2D, and FOXE3 in Pakistani families with clinically heterogeneous eye diseases

Abstract

Significant number out of 2.2 billion vision impairments in the world can be attributed to genetics. The current study is aimed to decipher the genetic basis of Leber congenital Amaurosis (LCA), Anterior Segment dysgenesis (ASD), and Retinitis Pigmentosa (RP), segregating in four large consanguineous Pakistani families. The exome sequencing followed by segregation analysis via Sanger sequencing revealed the LCA phenotypes segregating in families GCUF01 and GCUF04 can be attributed to c.465G>T (p.(Gln155His)) missense and novel c.139_140delinsA p.(Pro47Trhfster38) frameshift variant of AIPL1 and GUCY2D, respectively. The c.1843A>T (p.(Lys615*) truncating allele of MERTK is homozygous in all the affected individuals, presumably suffering with RP, of the GCUF02 family. Meanwhile, co-segregation of the ASD phenotype and the c.289A>G (p.(Ile97Val)) variant of FOXE3 was found in the GCUF06 family. All the identified variants were either absent or present in very low frequencies in the control databases. Our in-silico analyses and 3D molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MERTK, GUCY2D, and FOXE3 were categorized as "pathogenic" or "likely pathogenic", while the missense variant found in AIPL1 was deemed to have "uncertain significance" based upon the variant pathogenicity guidelines from the American College of Medical Genetics and Genomics (ACMG). This paper highlights the genetic diversity of vision disorders in the Pakistani population and reports the identification of four novel mutations in families who segregate clinically heterogeneous eye diseases. Our results give insight into the genotype-phenotype correlations of AIPL1, FOXE3, MERTK, and GUCY2D variants.

Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia

“…A homozygous missense variant (p.(Glu103Lys)) was reported in FOXE3 in patients underlying autosomal recessive congenital cataracts 37 . Recently, a homozygous missense variant (p.(Ile97Val)) in FOXE3 underlying congenital anterior segment dysgenesis, keratoconus, congenital bilateral corneal haze and apparent microphthalmia in five affected individuals belonging to a large consanguineous Pakistani family was reported by Rashid et al 38 Here, we present another Pakistani family with six affected individuals showing syndromic features (anophthalmia associated with other sensory processing disorders including sensorineural hearing loss, aphasia, developmental delay, behavioral issue and microcephaly) caused by a novel nonsense p.Glu36* variant in FOXE3 and a missense variant in AP4M1 . The inter‐ and intra‐familial variability in the phenotypes of present and previous cases might be a result of different familial backgrounds, age of the patients, nature and position of the variants, and/or dual molecular diagnosis.…”

Combined Single Gene Testing and Genome Sequencing as an Effective Diagnostic Approach for Anophthalmia and Microphthalmia Patients

“…This suggests that this variant could be a founder variant inherited from a common ancestor. The known pathogenic variants previously identified in FOXE3 are predominantly responsible for causing aphakia, sclerocornea, microphthalmia, anterior segment dysgenesis, and, rarely, increased intraocular pressure, bilateral congenital cataract, and vitreoretinal dysplasia [ 24 , 34 , 36 , 37 ]. In family MA201, we observed microphthalmia with corneal opacity.…”

Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders

“…PDE6 is a known Hsp90 client, and prolonged treatment with Hsp90 inhibitors results in reduced PDE6 levels ( Aguila et al, 2014 ). Mutations in AIPL1 are associated with Leber congenital amaurosis, a severe form of inherited retinal degeneration ( Yadav et al, 2017 ; Rashid et al, 2020 ; Sacristan-Reviriego et al, 2020 ; Xu et al, 2020 ). Mice lacking AIPL1 serve as a disease model of Leber congenital amaurosis.…”