Application of WES Towards Molecular Investigation of Congenital Cataracts: Identification of Novel Alleles and Genes in a Hospital-Based Cohort of South India

Dinesh Kumar Kandaswamy, Makarla Venkata Sathya Prakash, Jochen Graw, Samuel Koller, István Magyar, Amit Tiwari, Wolfgang Berger, Sathiyaveedu Thyagarajan Santhiya, Dinesh Kumar Kandaswamy, Makarla Venkata Sathya Prakash, Jochen Graw, Samuel Koller, István Magyar, Amit Tiwari, Wolfgang Berger, Sathiyaveedu Thyagarajan Santhiya

Abstract

Congenital cataracts are the prime cause for irreversible blindness in children. The global incidence of congenital cataract is 2.2-13.6 per 10,000 births, with the highest prevalence in Asia. Nearly half of the congenital cataracts are of familial nature, with a predominant autosomal dominant pattern of inheritance. Over 38 of the 45 mapped loci for isolated congenital or infantile cataracts have been associated with a mutation in a specific gene. The clinical and genetic heterogeneity of congenital cataracts makes the molecular diagnosis a bit of a complicated task. Hence, whole exome sequencing (WES) was utilized to concurrently screen all known cataract genes and to examine novel candidate factors for a disease-causing mutation in probands from 11 pedigrees affected with familial congenital cataracts. Analysis of the WES data for known cataract genes identified causative mutations in six pedigrees (55%) in PAX6, FYCO1 (two variants), EPHA2, P3H2,TDRD7 and an additional likely causative mutation in a novel gene NCOA6, which represents the first dominant mutation in this gene. This study identifies a novel cataract gene not yet linked to human disease. NCOA6 is a transcriptional coactivator that interacts with nuclear hormone receptors to enhance their transcriptional activator function.

Keywords: EPHA2; FYCO1; NCOA6; P3H2; PAX6; TDRD7; WES; clinical heterogeneity; congenital cataract; genetic heterogeneity; hearing and speech impairment.

Conflict of interest statement

The authors declare no competing interest.

Figures

Figure 1
Figure 1
The pedigree of DKEC4 (A). Eye picture of the proband’s (IV:1) right eye (B) and left eye (C) depicting posterior subcapsular cataracts. Partial sequence chromatogram of the DKEC4 family members, TDRD7 exon 16, depicting a homozygous mutation (c.3012 del; p.Val1005Tyrfs*4) in the proband ((D)—IV:1). Other family members: mother ((E)—III:4), father ((F)—III:3) and grandmother ((G)—II:7) were heterozygous for this variant control subject (H), showing a wildtype sequence. Site of mutation marked by an arrow. Mutational consequence leading to frame shift (in red) compared with wildtype sequence (in green) (I). Amino acid sequence alignment of human TDRD7 and orthologs from other species, showing a conservation of p.V10005 (encircled in red) (J). Divergent amino acid residues are shaded in a white color background.
Figure 1
Figure 1
The pedigree of DKEC4 (A). Eye picture of the proband’s (IV:1) right eye (B) and left eye (C) depicting posterior subcapsular cataracts. Partial sequence chromatogram of the DKEC4 family members, TDRD7 exon 16, depicting a homozygous mutation (c.3012 del; p.Val1005Tyrfs*4) in the proband ((D)—IV:1). Other family members: mother ((E)—III:4), father ((F)—III:3) and grandmother ((G)—II:7) were heterozygous for this variant control subject (H), showing a wildtype sequence. Site of mutation marked by an arrow. Mutational consequence leading to frame shift (in red) compared with wildtype sequence (in green) (I). Amino acid sequence alignment of human TDRD7 and orthologs from other species, showing a conservation of p.V10005 (encircled in red) (J). Divergent amino acid residues are shaded in a white color background.
Figure 1
Figure 1
The pedigree of DKEC4 (A). Eye picture of the proband’s (IV:1) right eye (B) and left eye (C) depicting posterior subcapsular cataracts. Partial sequence chromatogram of the DKEC4 family members, TDRD7 exon 16, depicting a homozygous mutation (c.3012 del; p.Val1005Tyrfs*4) in the proband ((D)—IV:1). Other family members: mother ((E)—III:4), father ((F)—III:3) and grandmother ((G)—II:7) were heterozygous for this variant control subject (H), showing a wildtype sequence. Site of mutation marked by an arrow. Mutational consequence leading to frame shift (in red) compared with wildtype sequence (in green) (I). Amino acid sequence alignment of human TDRD7 and orthologs from other species, showing a conservation of p.V10005 (encircled in red) (J). Divergent amino acid residues are shaded in a white color background.
Figure 2
Figure 2
Pedigree of C343 (A). Partial sequence chromatogram of C343 family members, PAX6 exon 7, depicting a heterozygous mutation (c.233 G > T; p.G78V) in the proband’s father ((B), II:17) and control subject (C). Mutant and wildtype peaks “T” and “G” are marked by an arrow. Missense mutation (in red) compared with the wildtype sequence (in green) (D). Model structure representing wildtype (E) versus mutant (F) PAX6. The mutated amino acid is highlighted in red, while its interacting amino acids nearby are marked in a white and blue combination. The mutated amino acid hinders the exposure of neighboring residues such as threonine at position 77 and tyrosine at position 75 and, also, alters other interactions, which might affect its interaction with its downstream targets. RFLP analysis of the mutation p.G78V in PAX6 (G), which shows co-segregation of the heterozygous mutation among affected family members (C2 and C6-C9). Unaffected family members (C3-C5) and control (DKC192) (C10) show complete digestion. C1—undigested PCR product. Amino acid sequence alignment of human PAX6 and orthologs from other species (H), showing the conservation of p.G78 (encircled in red). Divergent amino acid residues are shaded in a white background.
Figure 2
Figure 2
Pedigree of C343 (A). Partial sequence chromatogram of C343 family members, PAX6 exon 7, depicting a heterozygous mutation (c.233 G > T; p.G78V) in the proband’s father ((B), II:17) and control subject (C). Mutant and wildtype peaks “T” and “G” are marked by an arrow. Missense mutation (in red) compared with the wildtype sequence (in green) (D). Model structure representing wildtype (E) versus mutant (F) PAX6. The mutated amino acid is highlighted in red, while its interacting amino acids nearby are marked in a white and blue combination. The mutated amino acid hinders the exposure of neighboring residues such as threonine at position 77 and tyrosine at position 75 and, also, alters other interactions, which might affect its interaction with its downstream targets. RFLP analysis of the mutation p.G78V in PAX6 (G), which shows co-segregation of the heterozygous mutation among affected family members (C2 and C6-C9). Unaffected family members (C3-C5) and control (DKC192) (C10) show complete digestion. C1—undigested PCR product. Amino acid sequence alignment of human PAX6 and orthologs from other species (H), showing the conservation of p.G78 (encircled in red). Divergent amino acid residues are shaded in a white background.
Figure 2
Figure 2
Pedigree of C343 (A). Partial sequence chromatogram of C343 family members, PAX6 exon 7, depicting a heterozygous mutation (c.233 G > T; p.G78V) in the proband’s father ((B), II:17) and control subject (C). Mutant and wildtype peaks “T” and “G” are marked by an arrow. Missense mutation (in red) compared with the wildtype sequence (in green) (D). Model structure representing wildtype (E) versus mutant (F) PAX6. The mutated amino acid is highlighted in red, while its interacting amino acids nearby are marked in a white and blue combination. The mutated amino acid hinders the exposure of neighboring residues such as threonine at position 77 and tyrosine at position 75 and, also, alters other interactions, which might affect its interaction with its downstream targets. RFLP analysis of the mutation p.G78V in PAX6 (G), which shows co-segregation of the heterozygous mutation among affected family members (C2 and C6-C9). Unaffected family members (C3-C5) and control (DKC192) (C10) show complete digestion. C1—undigested PCR product. Amino acid sequence alignment of human PAX6 and orthologs from other species (H), showing the conservation of p.G78 (encircled in red). Divergent amino acid residues are shaded in a white background.
Figure 3
Figure 3
Pedigree of CCE13 (A). Partial sequence chromatogram of the proband ((B), IV:1) and control subject (C), EPHA2 exon 3, depicting a homozygous mutation (c.785G > A; p.Cys262Tyr). Mutant and wildtype nucleotide peaks “A” and “G” marked by an arrow. Missense mutation (red) compared with wildtype sequence (green) (D). RFLP analysis of the mutation p.C262Y in EPHA2 (E), which shows co-segregation of the homozygous mutation among affected family members (IV:1 and IV:2). Unaffected mother as the carrier (III:3). Control (DKC192) (CTRL) shows no digestion. UD—undigested PCR Product. Amino acid sequence alignment of human EPHA2 and orthologs from other species (F), showing conservation of p.C262 (encircled in red). Divergent amino acid residues are shaded in a white background. Model structure representing wildtype (G) and mutant (H) EPHA2. The mutated amino acid site is marked in red, while its interacting amino acids at the neighborhood are marked in a white and blue combination. The large physiochemical difference between cysteine and tyrosine alters its interactions with neighboring amino acids, which changes the structural confirmation of the protein. Secondary structure alterations were seen.
Figure 3
Figure 3
Pedigree of CCE13 (A). Partial sequence chromatogram of the proband ((B), IV:1) and control subject (C), EPHA2 exon 3, depicting a homozygous mutation (c.785G > A; p.Cys262Tyr). Mutant and wildtype nucleotide peaks “A” and “G” marked by an arrow. Missense mutation (red) compared with wildtype sequence (green) (D). RFLP analysis of the mutation p.C262Y in EPHA2 (E), which shows co-segregation of the homozygous mutation among affected family members (IV:1 and IV:2). Unaffected mother as the carrier (III:3). Control (DKC192) (CTRL) shows no digestion. UD—undigested PCR Product. Amino acid sequence alignment of human EPHA2 and orthologs from other species (F), showing conservation of p.C262 (encircled in red). Divergent amino acid residues are shaded in a white background. Model structure representing wildtype (G) and mutant (H) EPHA2. The mutated amino acid site is marked in red, while its interacting amino acids at the neighborhood are marked in a white and blue combination. The large physiochemical difference between cysteine and tyrosine alters its interactions with neighboring amino acids, which changes the structural confirmation of the protein. Secondary structure alterations were seen.
Figure 4
Figure 4
Pedigree of CCE27 (A). Partial sequence chromatogram of the proband ((B), IV:1) and control subject (C), P3H2 exon 9, depicting a homozygous mutation (c.1417 dup; p.Glu473Glyfs*19). Mutant and wildtype peaks are marked by an arrow. RFLP analysis of the mutation p.Glu473Glyfs*19 in P3H2 (D), which shows co-segregation among the affected family members (IV:1 and IV:2), while the parents are carriers (III:1 and III:2). Control (DKC192) (CTRL) shows complete digestion. UD—undigested PCR Product. The variation leading to frame shift mutation (red) compared with the wildtype sequence (green) (E).
Figure 4
Figure 4
Pedigree of CCE27 (A). Partial sequence chromatogram of the proband ((B), IV:1) and control subject (C), P3H2 exon 9, depicting a homozygous mutation (c.1417 dup; p.Glu473Glyfs*19). Mutant and wildtype peaks are marked by an arrow. RFLP analysis of the mutation p.Glu473Glyfs*19 in P3H2 (D), which shows co-segregation among the affected family members (IV:1 and IV:2), while the parents are carriers (III:1 and III:2). Control (DKC192) (CTRL) shows complete digestion. UD—undigested PCR Product. The variation leading to frame shift mutation (red) compared with the wildtype sequence (green) (E).
Figure 5
Figure 5
Pedigree of ACR12 (A). Eye picture of the proband (IV:1)—right eye (B) depicting posterior cortical cataracts and left eye (C) depicting Lamellar cataracts. Partial sequence chromatograms of the proband ((D), IV:1) and control subject (E), FYCO1 exon 8, depicting a homozygous mutation (c.2935C > T; p.Gln979*). Mutant and wildtype nucleotide peaks “T” and “C” marked by an arrow. Mutational consequence leading to truncation (in red) compared with the wildtype sequence (in green) (F). RFLP analysis of the mutation p.Gln979* in FYCO1 (G), which shows co-segregation among the affected family members (IV:1 and IV:2). Unaffected parents are carriers (III:3 and III:4). Control (CTRL-DKC190) shows complete digestion. UD—undigested PCR product of the control sample. Amino acid sequence alignment of human FYCO1 and orthologs from other species (H) showing the conservation of p.Q979 (encircled in red).
Figure 5
Figure 5
Pedigree of ACR12 (A). Eye picture of the proband (IV:1)—right eye (B) depicting posterior cortical cataracts and left eye (C) depicting Lamellar cataracts. Partial sequence chromatograms of the proband ((D), IV:1) and control subject (E), FYCO1 exon 8, depicting a homozygous mutation (c.2935C > T; p.Gln979*). Mutant and wildtype nucleotide peaks “T” and “C” marked by an arrow. Mutational consequence leading to truncation (in red) compared with the wildtype sequence (in green) (F). RFLP analysis of the mutation p.Gln979* in FYCO1 (G), which shows co-segregation among the affected family members (IV:1 and IV:2). Unaffected parents are carriers (III:3 and III:4). Control (CTRL-DKC190) shows complete digestion. UD—undigested PCR product of the control sample. Amino acid sequence alignment of human FYCO1 and orthologs from other species (H) showing the conservation of p.Q979 (encircled in red).
Figure 5
Figure 5
Pedigree of ACR12 (A). Eye picture of the proband (IV:1)—right eye (B) depicting posterior cortical cataracts and left eye (C) depicting Lamellar cataracts. Partial sequence chromatograms of the proband ((D), IV:1) and control subject (E), FYCO1 exon 8, depicting a homozygous mutation (c.2935C > T; p.Gln979*). Mutant and wildtype nucleotide peaks “T” and “C” marked by an arrow. Mutational consequence leading to truncation (in red) compared with the wildtype sequence (in green) (F). RFLP analysis of the mutation p.Gln979* in FYCO1 (G), which shows co-segregation among the affected family members (IV:1 and IV:2). Unaffected parents are carriers (III:3 and III:4). Control (CTRL-DKC190) shows complete digestion. UD—undigested PCR product of the control sample. Amino acid sequence alignment of human FYCO1 and orthologs from other species (H) showing the conservation of p.Q979 (encircled in red).
Figure 6
Figure 6
Pedigree of BCC23 (A). Clinical phenotype of probands (IV:8): right eye depicting posterior subcapsular cataracts (B) upon retro-illumination. Partial sequence chromatogram of BCC23 family members, FYCO1 exon 17, depicting a homozygous mutation (c.4288_4290del; ΔE1430) in the proband’s brother (IV:10) (C), and control subject (D) showing a wildtype sequence. Site of mutation was marked by an arrow. The mutation leads to an in-frame deletion of a single amino acid (marked in red) compared with the wildtype sequence (marked in green) (E). Amino acid sequence alignment of human FYCO1 and orthologs from other species (F), showing a conservation of p.E1430 (encircled in red). Partial sequence chromatograms (reverse) of the proband’s affected brother ((G), IV:10) and control subject (H), NCOA6 exon 9, depicting a homozygous mutation (c.1790G > A; p.Gly597Asp). Mutant and wildtype peaks “T” and “C” marked by an arrow. Missense mutation (marked in red) compared with the wildtype sequence (marked in green) (I). RFLP analysis (J) of the variant allele p.Gly597Asp in NCOA6, which shows co-segregation among the affected family members (IV:9 and IV:10). Unaffected father (III:6) and control (CTRL-DKC190) shows complete digestion, indicating a wildtype sequence. UD—undigested PCR product. Amino acid sequence alignment of human NCOA6 and orthologs from other species, showing a conservation of p.G596 (encircled in red). Divergent amino acid residues are shaded in a white background (K).
Figure 6
Figure 6
Pedigree of BCC23 (A). Clinical phenotype of probands (IV:8): right eye depicting posterior subcapsular cataracts (B) upon retro-illumination. Partial sequence chromatogram of BCC23 family members, FYCO1 exon 17, depicting a homozygous mutation (c.4288_4290del; ΔE1430) in the proband’s brother (IV:10) (C), and control subject (D) showing a wildtype sequence. Site of mutation was marked by an arrow. The mutation leads to an in-frame deletion of a single amino acid (marked in red) compared with the wildtype sequence (marked in green) (E). Amino acid sequence alignment of human FYCO1 and orthologs from other species (F), showing a conservation of p.E1430 (encircled in red). Partial sequence chromatograms (reverse) of the proband’s affected brother ((G), IV:10) and control subject (H), NCOA6 exon 9, depicting a homozygous mutation (c.1790G > A; p.Gly597Asp). Mutant and wildtype peaks “T” and “C” marked by an arrow. Missense mutation (marked in red) compared with the wildtype sequence (marked in green) (I). RFLP analysis (J) of the variant allele p.Gly597Asp in NCOA6, which shows co-segregation among the affected family members (IV:9 and IV:10). Unaffected father (III:6) and control (CTRL-DKC190) shows complete digestion, indicating a wildtype sequence. UD—undigested PCR product. Amino acid sequence alignment of human NCOA6 and orthologs from other species, showing a conservation of p.G596 (encircled in red). Divergent amino acid residues are shaded in a white background (K).
Figure 6
Figure 6
Pedigree of BCC23 (A). Clinical phenotype of probands (IV:8): right eye depicting posterior subcapsular cataracts (B) upon retro-illumination. Partial sequence chromatogram of BCC23 family members, FYCO1 exon 17, depicting a homozygous mutation (c.4288_4290del; ΔE1430) in the proband’s brother (IV:10) (C), and control subject (D) showing a wildtype sequence. Site of mutation was marked by an arrow. The mutation leads to an in-frame deletion of a single amino acid (marked in red) compared with the wildtype sequence (marked in green) (E). Amino acid sequence alignment of human FYCO1 and orthologs from other species (F), showing a conservation of p.E1430 (encircled in red). Partial sequence chromatograms (reverse) of the proband’s affected brother ((G), IV:10) and control subject (H), NCOA6 exon 9, depicting a homozygous mutation (c.1790G > A; p.Gly597Asp). Mutant and wildtype peaks “T” and “C” marked by an arrow. Missense mutation (marked in red) compared with the wildtype sequence (marked in green) (I). RFLP analysis (J) of the variant allele p.Gly597Asp in NCOA6, which shows co-segregation among the affected family members (IV:9 and IV:10). Unaffected father (III:6) and control (CTRL-DKC190) shows complete digestion, indicating a wildtype sequence. UD—undigested PCR product. Amino acid sequence alignment of human NCOA6 and orthologs from other species, showing a conservation of p.G596 (encircled in red). Divergent amino acid residues are shaded in a white background (K).
Figure 6
Figure 6
Pedigree of BCC23 (A). Clinical phenotype of probands (IV:8): right eye depicting posterior subcapsular cataracts (B) upon retro-illumination. Partial sequence chromatogram of BCC23 family members, FYCO1 exon 17, depicting a homozygous mutation (c.4288_4290del; ΔE1430) in the proband’s brother (IV:10) (C), and control subject (D) showing a wildtype sequence. Site of mutation was marked by an arrow. The mutation leads to an in-frame deletion of a single amino acid (marked in red) compared with the wildtype sequence (marked in green) (E). Amino acid sequence alignment of human FYCO1 and orthologs from other species (F), showing a conservation of p.E1430 (encircled in red). Partial sequence chromatograms (reverse) of the proband’s affected brother ((G), IV:10) and control subject (H), NCOA6 exon 9, depicting a homozygous mutation (c.1790G > A; p.Gly597Asp). Mutant and wildtype peaks “T” and “C” marked by an arrow. Missense mutation (marked in red) compared with the wildtype sequence (marked in green) (I). RFLP analysis (J) of the variant allele p.Gly597Asp in NCOA6, which shows co-segregation among the affected family members (IV:9 and IV:10). Unaffected father (III:6) and control (CTRL-DKC190) shows complete digestion, indicating a wildtype sequence. UD—undigested PCR product. Amino acid sequence alignment of human NCOA6 and orthologs from other species, showing a conservation of p.G596 (encircled in red). Divergent amino acid residues are shaded in a white background (K).

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