Table 1.
Chromosomal loci reported to show evidence of a linkage with keratoconus (data shown in chronological order)
| Locus | Population | No. of families/inheritance | No. of individuals (no. of affected individuals) | No. of markers used for initial mapping | LOD | NPL | Positional candidate genes | Screened genes (method) | Detected mutations | References |
|---|---|---|---|---|---|---|---|---|---|---|
| 17p13a | Pakistani | 1/ARb | 15 (4) | 150 Microsatellite markers | 3.21 | – | RETGC-1, PEDF | RETGC-1, PEDF (Sanger sequencing) | No mutations | Hameed et al. (2000) |
| 16q22.3-q23.1 | Northern Finnish | 20/ADc | 76 (42) | 292 Microsatellite markers | 4.11 | 3.27 | LCAT, TAT, CHST6 | – | – | Tyynismaa et al. (2002) |
| 20q12 | Northwest Tasmanian | – | 8 (8) | 343 Dinucleotide repeat markers | – | – | MMP9 | MMP9 (cSNP analysis) | No mutations | Fullerton et al. (2002) |
| 15q22.33-24.2d | Northern Irish | 1/AD | 30 (16) | 350 Microsatellite markers | 8.13 | – | CTSH, CRABP1, IREB2, RASGRF1 | CTSH, CRABP1, IREB2, RASGRF1, ORF4L1, KIAA1055, ETFA, AWP1, REC14, KIAA1199, RCN2, FAH, IDH3A, MTHFS, ADAMTS7, MAN2C1, PTPN9, KIAA1024, ARNT2, BCL2A1, ISL2, C15ORF22 (P24B), DNAJA4, FLJ14594, CIB2 (KIP2), C15ORF5, PSMA4, miR184 (Sanger sequencing) | mir184 c.57C>T | Hughes et al. (2003), Dash et al. (2006), Hughes et al. (2011) |
| 3p14-q13 | Italian | 1/AD | 21 (10) | 380 Markers | 3.09 | – | COL8A1 | COL8A1 (Sanger sequencing) | No mutations | Brancati et al. (2004), Aldave et al. (2007) |
| 5q14.1-q21.1 | Caucasian | 1/AD | 27 (14) | 343 Microsatellite markers | 3.48 | – | CAST, ARTS-1, PCSK1 | CAST (TaqMan genotyping) | CAST c.-40+7414T>C | Tang et al. (2005), Li et al. (2013b) |
| 2p24 | European, Arab, and Caribbean African | 28/AD | 216 (112) | 382 Microsatellite markers | 5.12 | – | OSR1, RhoB, GDF-7, FLJ21820, FLJ14249 | – | – | Hutchings et al. (2005) |
| 2q | Hispanic | 17/AD | 93 (≥17 sib pairs) | 380 Microsatellite markers | 2.3 | 0.96 | – | – | – | Li et al. (2006) |
| 3p | Hispanic | 17/AD | 93 (≥17 sib pairs) | 380 Microsatellite markers | 2.2 | 1.69 | – | – | – | Li et al. (2006) |
| 4q | Caucasian/Hispanic | 67/AD | 351 (110 sib pairs) | 380 Microsatellite markers | 2.2 | 2.68 | – | – | – | Li et al. (2006) |
| 5q31 | Caucasian/Hispanic | 67/AD | 351 (110 sib pairs) | 380 Microsatellite markers | 2.01 | 2.90 | – | – | – | Li et al. (2006) |
| 5p | Hispanic | 17/AD | 93 (≥17 sib pairs) | 380 Microsatellite markers | 2.5 | 2.64 | – | – | – | Li et al. (2006) |
| 9p | Hispanic | 17/AD | 93 (≥17 sib pairs) | 380 Microsatellite markers | 3.8 | 3.55 | – | – | – | Li et al. (2006) |
| 9q34 | Caucasian/Hispanic | 67/AD | 351 (110 sib pairs) | 380 Microsatellite markers | 3.5 | 2.83 | GSN | – | – | Li et al. (2006) |
| 11p | Caucasian | 40/AD | 217 (≥40 sib pairs) | 380 Microsatellite markers | 2.3 | 1.98 | – | – | – | Li et al. (2006) |
| 12p | Caucasian/Hispanic | 67/AD | 351 (110 sib pairs) | 380 Microsatellite markers | 2.5 | 2.64 | – | – | – | Li et al. (2006) |
| 14q | Caucasian/Hispanic | 67/AD | 351 (110 sib pairs) | 380 Microsatellite markers | 2.6 | 2.23 | – | – | – | Li et al. (2006) |
| 17q | Hispanic | 17/AD | 93 (≥17 sib pairs) | 380 Microsatellite markers | 3.9 | 3.32 | – | – | – | Li et al. (2006) |
| 1p36.23-36.21 | Australian | 1/AD | 11 (9) | 10,000 SNP markers | 1.94/3.4e | 7.8e | ENO1, CTNNBIP1, PLOD1, UBIAD1, SPSB1 | ENO1, CTNNBIP1, PLOD1, UBIAD1, SPSB1 (Sanger sequencing) | No mutations | Burdon et al. (2008) |
| 8q13.1-q21.11 | Australian | 1/AD | 11 (9) | 10,000 SNP markers | 1.96/3.4e | 7.8e | TCEB1 | TCEB1 (Sanger sequencing) | No mutations | Burdon et al. (2008) |
| 5q21.2 | Southern Italian | 25/AD | 136 (77) | 382 Highly polymorphic markers | 0.49 | 2.73 | LOX | – | – | Bisceglia et al. (2009) |
| 5q32-q33 | Southern Italian | 25/AD | 136 (77) | 382 Highly polymorphic markers | 2.45 | 3.22 | SPARC | – | – | Bisceglia et al. (2009) |
| 9q21.13 | Southern Italian | 25/AD | 136 (77) | 382 Highly polymorphic markers | 1.07 | 1.93 | ANXA1 | – | – | Bisceglia et al. (2009) |
| 9q22.2 | Southern Italian | 25/AD | 136 (77) | 382 Highly polymorphic markers | 1.61 | 2.10 | CTSL,PCSK5 | – | – | Bisceglia et al. (2009) |
| 14q11.2 | Southern Italian | 25/AD | 136 (77) | 382 Highly polymorphic markers | 2.09 | 2.62 | APEX1 | – | – | Bisceglia et al. (2009) |
| 15q15.1 | Southern Italian | 25/AD | 136 (77) | 382 Highly polymorphic markers | 1.74 | 2.32 | – | – | – | Bisceglia et al. (2009) |
| 16q23.1 | Southern Italian | 25/AD | 136 (77) | 382 Highly polymorphic markers | 0.45 | 1.97 | CDK10 | – | – | Bisceglia et al. (2009) |
| 18p11.31 | Southern Italian | 25/AD | 136 (77) | 382 Highly polymorphic markers | 0.72 | 2.00 | – | – | – | Bisceglia et al. (2009) |
| 13q32 | Ecuadorian | 18/AD | 143 (76) | 763 Fluorescently labeled PCR primer pairs | 4.1 | 3.2 | MBNL1, IPO5, FARP1, RNF113B, STK24, DOCK9, ZIC5, ZIC2 | MBNL1, IPO5, FARP1, RNF113B, STK24, DOCK9, ZIC5, ZIC2 (Sanger sequencing) |
DOCK9 c.2262A>C DOCK9 c.720+43A>G IPO5 c.2377-132A>C STK24 c.1053+29G>C |
Gajecka et al. (2009), Czugala et al. (2012), Karolak et al. (2016b) |
| 13q34 | Ecuadorian | 18/AD | 143 (76) | 763 Fluorescently labeled PCR primer pairs | 2.86 | – | COL4A1, COL4A2 | COL4A1, COL4A2 (Sanger sequencing) | No mutations | Gajecka et al. (2009) Karolak et al. (2011) |
| 14q24.3 | White English, Iranian, Indian, Pakistani | 6/AD | 35 (23) | 10,805 SNP markers | 3.58 | – | VSX2 | VSX2 (Sanger sequencing) | No mutations | Liskova et al. 2010 |
| 5q31 | Ecuadorian | 1/AD | 8 (6) | 811 Microsatellite markers | 2.32 | 0.53 | PITX1, IL9, TGFBI | PITX1, IL9, TGFBI (Sanger sequencing) | No mutations | Rosenfeld et al. (2011), Karolak et al. (2016b) |
| 11p15.5-p15.4 | Ecuadorian | 1/AD | 20 (7) | 811 Microsatellite markers | – | 1.66 | – | – | – | Nowak et al. (2012) |
| 2q13-q14.3 | Ecuadorian | 1/AD | 21 (9) | 811 Microsatellite markers | – | 2.39 | IL1A, IL1B, IL1RN | IL1A, IL1B, IL1RN (Sanger sequencing) | IL1RN c.214+242C>T | Nowak et al. (2013) |
| 20p13-p12.2 | Ecuadorian | 1/AD | 21 (9) | 811 Microsatellite markers | – | 2.40 | SLC4A11 | SLC4A11 (Sanger sequencing) | SLC4A11 c.2558+149_2558+203del54 | Nowak et al. (2013) |
| 5q15-q21.1 | Caucasian | 1/AD | 27 (14) | 525,000 SNP markers | 2.49 | – | – | – | – | Bykhovskaya et al. (2016) |
aKeratoconus with Leber congenital amaurosis
bAR: Autosomal recessive mode of inheritance
cAD: Autosomal dominant mode of inheritance
dKeratoconus with cataract
eDigenic approach