Balkan Journal of Medical Genetics

GENE MAPPING IN AN ANOPHTHALMIC PEDIGREE OF A CONSANGUINEOUS PAKISTANI FAMILY OPENED NEW HORIZONS FOR RESEARCH
Saleha S, Ajmal M, Zafar S, Hameed A
*Corresponding Author: Dr. Shamim Saleha, Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology, Kohat 26000, Khyber Paktunkhwa, Pakistan. Tel: +92-922-5291-4659. Cell: +92-333-964-2532. Fax: +92-922-554-556. E-mail: shamimsaleha@yahoo.com
page: 77

DISCUSSION

The term clinical anophthalmia was first used by Duke-Elder [8], and is a rare disease. The reported average prevalence of congenital anophthalmia is three in 100,000 [14]. Clinical anophthalmia is the absence of the eye and diagnosed without histological examination [22]. The most common phenotype in affected individuals is bilateral anophthalmia [4], and unilateral anophthalmia may rarely be seen [5]. In the present study, we reported a consanguineous family with two affected daughters of isolated clinical anophthalmia from the Kohat region of Khyber Pakhtunkhwa, Pakistan. Affected daughters do not have any congenital malformations except for bilateral clinical anophthalmia. In addition, the family history showed that there was no other member with anophthalmia. In the pedigree under study, the affected daughters have unaffected parents, who are first cousins, thus inheritance is undoubtedly autosomal recessive. Moreover, members of this family practiced consanguineous marriages to follow the family tradition of marriages between cousins. Consanguinity in a family as a risk factor and consequently autosomal recessive mode of inheritance for clinical anophhalmia, has rarely been reported [1,8,10,11]. However, X-linked inher-itance has been described for clinical anophthalmia [4,23]. Epidemiological studies have also reported other risk factors including late maternal age, multiple births, low birth weight, premature birth complications, mechanical abortion and severe vitamin A deficiency [4,15,16,18]. These risk factors were not identified in this family as a cause of clinical anophthalmia. In the present study, linkage analysis of family was performed with STR markers corresponding to the candidate genes involved in clinical anophthalmia phenotypes. This Pakistani family was linked to a locus at chromosome 3q26.3-q27, which carries the SOX2 gene. The critical disease region was flanked by STR markers D3S1565 and D3S1311 in the affected daughters; therefore, it is probable that the disease gene lies between these two markers within a region of approximately 23 cM on chromosome 3. However, the affected daughters showed homozygosity in the disease region of approximately 3 cM for markers D3S 1262, D1S2436 and D3S1580. The linkage data presented in this study suggested that a gene for clinical anophthalmia was present within the region of homozygosity at chromosome 3. However, mutation screening did not reveal any mutation in the exonic sequence and regulatory element of the SOX2 gene in the parents and offspring of this family. This indicates that another gene might possibly be present in the mapped region for disease phenotype and needs to be identified and screened to identify the disease-associated mutation in this family. The Lod score calculation in linkage analysis is very successful in mapping Mendelian disease genes or to examine combined effects of genes. However, the Lod score could not be calculated, as there were only two affected daughters, and that is the limitation of our study. The severity of clinical anophthalmia is variable due to mutations in various human genes that are associated with anophthalmia [4,5]. Among these, the SOX2 has been reported as a major causative gene for clinical anophthalmia [4]. By genetic analysis, the single-exon SOX2 gene was identified in an intron of a noncoding SOX2OT (SOX2 overlapping transcript) gene [24]. By using the fluorescent in situ hybridization (FISH) approach, the SOX2 gene was mapped to chromosome 3q26.3-q27 [25]. The SOX2 gene is universally expressed in neural stem and neural precursor cells throughout the central nervous system including the neural retina [26-28], and mutations in this gene are common causes of retinal and ocular malformations in humans. By sequence analysis of the coding region of the SOX2 gene, a heterozygous loss-of-function mutation was identified in individuals with unilateral and bilateral anophthalmia in various research studies. By SOX2 mutation analysis in four unrelated individuals with unilateral or bilateral clinical anophthalmia, Fantes et al. [24] identified heterozygous de novo truncating mutations in the SOX2 gene. Similarly, in an 11-month-old Mexican female infant with bilateral clinical anophthalmia and brain malformations, Zenteno et al. [29] identified heterozygosity for a 20 bp deletion in the SOX2 gene. De novo missense mutations and frameshift mutations in the heterozygous state in the coding region of the SOX2 gene in patients with bilateral anophthalmia/ microphthalmia were also reported [30]. In a 12-year-old girl with congenital bilateral clinical anophthalmia, a heterozygous nonsense mutation in the SOX2 gene was found [31]. Similarly, a heterozygous missense mutation was found in the SOX2 gene in a girl with bilateral clinical anophthalmia. However, the clinically normal mother was found to be heterozygous for this mutation [32]. The SOX2 gene was analyzed in two female siblings with clinical bilateral anophthalmia and found heterozygosity for a 17 bp deletion on this gene [6,33]. Similarly, in an Italian male with clinical bilateral anophthalmia and micropenis, a heterozygous insertion mutation was reported in the SOX2 gene responsible for such phenotypes [34].

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