I= GENETIC EPIDEMIOLOGY AND MOLECULAR STUDIES OF NONSYNDROMIC DEAFENESS AT FAMILY LEVEL
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Title of Thesis
GENETIC EPIDEMIOLOGY AND MOLECULAR STUDIES OF NONSYNDROMIC DEAFENESS AT FAMILY LEVEL

Author(s)
Salma Sultana
Institute/University/Department Details
Department of Biological Sciences/ Quaid-i-Azam University Islamabad
Session
2004
Subject
Genetics
Number of Pages
151
Keywords (Extracted from title, table of contents and abstract of thesis)
nonsyndromic deafeness, genetic epidemiology, sheikh families, rajput family, dfnb28, dfnb12, dfnb37, dfnb21

Abstract
The present study includes five families from different areas of Pakistan. Of these, four Sheikh families (21 DF, 17 DF, 18 DF and 19 DF), residing in District Faisalabad and one Rajput family (15 DF), residing in District Rawalpindi, were diagnosed for prelingual, congenital, severe to profound, sensorineural autosomal recessive nonsyndromic deafness. Clinical assessment was obtained before carrying out linkage analysis at molecular level in these families. The aim of the present study was to obtain a base line information regarding the development of nonsyndromic deafness in some Pakistani families at molecular level.

Family-l (21 DF), spans on 5 generations and consists of 27 individuals. Of the 20 live members, 5 members were affected including 3 females and 2 males. The molecular studies were carried out at Biomedical and Genetic Engineering Division, KRL, Islamabad. Fifteen family members (5 affected and 10 normal) were processed for molecular studies. All marriages involved in the molecular study are consanguineous. Linkage analysis for known loci of autosomal recessive non-syndromic deafness was carried out. Significant linkage was found with DFNB28 locus (22q13). Two point lod score analysis resulted in maximum lod score (Z max) 4.35 for marker D22S445 at θ = 0.

Family-2 (17 DF), spans on 6 generations and consists of 53 individuals. Of the 36 live members, 8 members were affected including 2 females and 6 males, whereas 2 affected females were dead at the time of data collection. All marriages involved in the molecular study are consanguineous except one. Sixteen family members (6 affected and 7 normal) were processed for molecular studies. Linkage analysis for known loci of autosomal recessive non-syndromic deafness loci was carried out. Linkage was found with DFNB37 locus (6q13). Two point analysis resulted in maximum lod score (Z max) 3.78 for marker D6S 1031 at θ = 0.

Family-3 (15 DF), spans on 5 generations and consists of 51 individuals, of the 27 live members, 8 members were affected including 5 females and 3 males and one affected female was dead at the time of data collection. All marriages involved in the molecular study are consanguineous except one. Sixteen family members (eight affected and eight normal) were processed for molecular studies. Initially eight members were selected at random to find out to which marker linkage is associated.

Since, hint of linkage was obtained with marker DI0Sl432 (Zmax 2.06 at θ = 0). Then 16 family members were processed further for confirmation of linkage with marker D10S1432. Linkage studies revealed the presence of disease locus at DFNB 12 (10q21-22). Two point lod score gave maximum value of 3.81 at θ = 0, for micro satellite marker D10S1432.

Family-4 (18 DF), spans on 6 generations and consists of 41 individuals. Of the 18 live members, 5 members were affected including 4 males and 1 female, and 2 affected males were dead. All marriages involved in the molecular study are consanguineous except one. Twelve family members (5 affected and 7 normal) were processed for molecular studies. Initially eight members were selected at random to find out to which marker linkage is associated. Since, hint of linkage was obtained with marker D11S1998 (Zmax 1.36 at θ = 0). Then 12 family members were processed further for confirmation of linkage with marker D11S1998. Linkage studies revealed the presence of disease locus at DFNB21 (11q22-24). Two point lod score gave maximum value of3.21 at θ = 0, for microsatellite marker D11S1998.

Family-5 (19 DF), spans on five generations and consists of 39 individuals, of the 30 live members, 7 males were affected and 1 affected male was dead at the time of study. All marriages involved in the molecular study are consanguineous. Sixteen family members (7 affected and 9 normal) were processed for molecular studies. Initially eight members were selected at random to find out to which marker linkage is associated. Since, hint of linkage was obtained with marker D11S4464 (Zmax 1.37 at θ = 0). Then 16 family members were processed further for confirmation of linkage with marker D11S4464. Linkage studies revealed the presence of disease locus at DFNB21 (11q22-24). Two point lod score gave maximum value (Zmax) 3.03 at θ = 0, for micro satellite marker D11S4464.

The results show strong evidence that consanguineous marriages are of considerable clinical significance. The consanguinity contributes 29-71 % in the present study and it has been observed that due to consanguinity in all the families studied recessively inherited nonsyndromic deafness has been ascertained.

The loci investigated in this study (DFNB28, DFNB12, DFNB37, DFNB21) and their location (22q13, 10q21-22, 6q13, 11q23-25, respectively) were also reported from Palestine (Walsh et al. 2000); Pakistan, Turkey (Bork et al. 01.2001), Syria (Chaib et al. 1996b); Pakistan (Ahmed et al. 2003b) and Lebanon (Mustapha et al. 1999) reflects that migrations in these regions of population took place in the olden times. This has been identified by Quintana-Murci et al. (2001) that in what different ways human population occurred in South Western region. The similarity in disease locus and location of gene in this study may be related to the migrations in olden time.

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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
316.55 KB
2 1 Introduction 1
764.24 KB
3 2 Materials And Methods 25
305.83 KB
4 3 Results 33
1373.36 KB
5 4 Discussion 113
529.37 KB
6 5 References 129
588.14 KB