Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan
Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from PakistanAndres Veske+,, Ralph Oehlmann1,, Farah Younus2, Aisha Mohyuddin2, Bertram Müller-Myhsok1, S. Qasim Mehdi2 and Andreas Gal*
Institut für Humangenetik, Universitäts-Krankenhaus Eppendorf, Butenfeld 32, D-22529 Hamburg, Germany, 1Abteilung für Molekulargenetik, Bernhard Nocht Institut für Tropenmedizin, D-20359 Hamburg, Germany and 2Biomedical and Genetic Engineering Division, Khan Research Laboratories, Islamabad, Pakistan
Received September 5, 1995; Revised and Accepted October 9, 1995
Autosomal recessive childhood-onset non-syndromic deafness is one of the most frequent forms of inherited hearing impairment. Recently five different chromosomal regions, 7q31, 11q13.5, 13q12, 14q and the pericentromeric region of chromosome 17, have been shown to harbour disease loci for this type of neurosensory deafness. We have studied a large family from Pakistan, containing several consanguineous marriages and segregating for a recessive non-syndromic childhood-onset deafness. Linkage analysis mapped the disease locus (DFNB8) on the distal long arm of chromosome 21, most likely between D21S212 and D21S1225 with the highest lod score of 7.31 at [theta] = 0.00 for D21S1575 on 21q22.3.
Deafness is one of the most common human sensory defects affecting ~1 in 1000 live births and is inherited in more than half of the cases (for a recent review see ref. 1 ). There are many different forms of genetic deafness, some of which may themselves be heterogeneous, largely variable in expression and/or present with incomplete penetrance. In ~70% of the cases, genetic deafness is non-syndromic, that is it is not associated with other clinically recognizable features. The most common pattern of inheritance is autosomal recessive, accounting for >75% of the cases. Recently linkage analysis has led to the identification of five different chromosomal regions which harbour loci for recessive non-syndromic forms of deafness, 7q31, 11q13.5 (DFNB2),13q12 (DFNB1), 14q and the pericentromeric region of chromosome 17 (DFNB3) (2 -6 ).
Here we report linkage data suggesting that another recessive locus maps on the distal long arm of chromosome 21.
We have ascertained a large family (1DF) in Pakistan consisting of 41 members, of which eight are affected by a profound childhood-onset non-syndromic deafness. The age of onset of disease was 10-12 years and hearing was completely lost within 4-5 years. As shown in Figure 1 , the family contains several consanguineous marriages.
The linkage data presented in this communication suggest that a gene for autosomal recessive non-syndromic deafness is on the distal long arm of chromosome 21, most likely in 21q22.3. In case of recessive traits, the resolution power of genetic mapping by pairwise linkage data is largely limited both by the moderate total number of fully informative meioses as the genotype of healthy siblings at the disease locus can not be determined and by the possibility of non-allelic genetic heterogeneity. In case of consanguinity of the parents, all patients should be homozygous for a certain chromosomal region around the disease gene and genetic mapping can be further refined by the analysis of linkage disequilibrium and homozygosity-by-descent for alleles at closely linked polymorphic loci. In 1DF, several different possibilities should be considered to explain the absence of homozygosity for D21S1259, D21S171 and D21S1575 in the affected individuals in branch 2 of the family. As the two patients are related through their father with the rest of the kindred and because their alleles 3, 2 and 4 for D21S1259, D21S171 and D21S1575 respectively, are of paternal origin (Fig. 1 ), our assumption on close linkage between disease locus and the three loci will still hold. Alleles 2 (D21S1259), 4 (D21S171) and 6 (D21S1575) were transmitted to both patients in branch 2 from their mother who, according to the information given by the family, is not related to her husband. Yet, since they come from the same larger inbred `clan', the most likely possibility is that the mother is distantly related to the entire family and carries a recombinant chromosome 21 with alleles 2 (D21S1259), 4 (D21S171) and 6 (D21S1575) in phase with the mutant allele of the deafness gene. Alternatively, the mother may carry the same mutation having occurred independently or a different mutation of the same gene, in both cases on a different genetic background. Although it is not very likely, one can not exclude the possibility that the deafness of the two patients in branch 2 is due to a defect in another recessive gene. Examples of non-allelic genetic heterogeneity in extended consanguineous pedigrees segregating for autosomal recessive deafness (2 ) or for another extremely heterogeneous genetic disorder, retinitis pigmentosa, have been observed recently (9 ,10 ).
The location of a recessive deafness gene in 21q22.3 is further substantiated by an independent clinical observation. The locus (EPM1) for progressive myoclonic epilepsy of the Unverricht-Lundberg type, an autosomal recessive disorder of the central nervous system, has been mapped to 21q22.3 by linkage studies (11 ). Latham and Munro reported a complex syndrome in a family in which the parents were second cousins and five out of eight children had progressive myoclonic epilepsy and early-onset deafness (12 ). Assuming that this syndrome is due to a larger structural rearrangement (e.g. a deletion or inversion) of chromosome 21, these data also suggest that a gene for childhood-onset deafness is in 21q22.3, probably in the physical proximity of the gene for progressive myoclonic epilepsy.
All patients and their living relatives were examined by a specialist for audiometry. For patients, pure-tone audiometry was done in a `sound chamber' using a Glazer audiometer. Frequencies tested by bone and air conduction were 125, 250, 500, 1000, 2000, 4000 and 8000 Hz with intensities up to 120 dB (maximum audio threshold in both ears of patients in this family was 105 dB at 1000 Hz). The age of onset of the disease was 10-12 years. By age of 14-16 years thresholds were at severe levels across the entire frequency range leading to profound hearing loss. Audiometric configurations for both ears were similar with all deaf persons affected bilaterally.
Linkage analysis was done using MLINK (V 5.1) in its FASTLINK implementation (V 2.2). For the analysis, a disease allele frequency of 0.01 was assumed. The mode of inheritance was taken to be autosomal recessive. Due to computational complexity of the multiple inbred pedigree and the resulting excessive amounts of computing time needed, multipoint analysis was not feasible.
Genomic DNA was available from 24 family members indicated in Figure 1 . All polymorphic markers were typed using standard PCR amplification conditions. Upon a first indication of linkage to chromosome 21, the family was genotyped for a total of 25 chromosome 21-specific markers to map the disease locus as precisely as possible (Table 1 , Fig. 2 and data not shown).
This study was financially supported by the FAUN-Stiftung (Nürnberg, Germany) and a core grant from the Dr A. Q. Khan Research Laboratories, Government of Pakistan (S.Q.M.). This article is based in part on a doctoral study by A.V. in the Faculty of Biology, University of Hamburg.
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*To whom correspondence should be addressed
+On leave of absence from the Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
}Both authors have contributed equally to this work
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