A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation in a consanguineous Iranian family

The genetic basis of autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to suspect that the number of underlying gene defects may well go beyond 1,000. To date, however, only less than 10 genes have been implicated in non‐specific/non‐syndromic ARMR (NS‐ARMR). As part of an ongoing systematic study aiming to identify further ARMR genes, we investigated a consanguineous family with three patients with NS‐ARMR. By linkage analysis and subsequent mutation screening we identified a novel nonsense mutation (c.163C > T [p.Q55X]) in the second exon of the TUSC3 gene. This is the third MR causing defect in TUSC3 to be described and the second independent mutation in this gene in a cohort of more than 200 ARMR families from the Iranian population. This argues for a more prominent role of TUSC3 in the etiology of this genetically heterogeneous disorder as compared to most of the other so far identified ARMR genes. © 2011 Wiley‐Liss, Inc.     

Homozygosity mapping in outbred families with mental retardation

Autosomal recessive mental retardation (AR-MR) may account for up to 25% of genetic mental retardation (MR). So far, mapping of AR-MR genes in consanguineous families has resulted in six nonsyndromic genes, whereas more than 2000 genes might contribute to AR-MR. We propose to use outbred families with multiple affected siblings for AR-MR gene identification. Homozygosity mapping in ten outbred families with affected brother-sister pairs using a 250 K single nucleotide polymorphism array revealed on average 57 homozygous regions over 1 Mb in size per affected individual (range 20-74). Of these, 21 homozygous regions were shared between siblings on average (range 8-36). None of the shared regions of homozygosity (SROHs) overlapped with the nonsyndromic genes. A total of 13 SROHs had an overlap with previously reported loci for AR-MR, namely with MRT8, MRT9, MRT10 and MRT11. Among these was the longest observed SROH of 11.0 Mb in family ARMR1 on chromosome 19q13, which had 2.9 Mb (98 genes) in common with the 5.4 Mb MRT11 locus (195 genes). These data support that homozygosity mapping in outbred families may contribute to identification of novel AR-MR genes.     

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

Non-specific intellectual disability of autosomal recessive inheritance (NS-ARID) represents an important fraction of severe cognitive dysfunction disorders. To date, only 10 genes have been identified, and further 24 linked-ARID loci have been reported, as well as others with suggestive linkage. To discover novel genes causing NS-ARID, we undertook genome-wide homozygosity mapping in 64 consanguineous multiplex families of Syrian descent. A total of 11 families revealed unique, significantly linked loci at 4q26-4q28 (MRT17), 6q12-q15 (MRT18), 18p11 (MRT19), 16p12-q12 (MRT20), 11p15 (MRT21), 11p13-q14 (MRT23), 6p12 (MRT24), 12q13-q15 (MRT25), 14q11-q12 (MRT26), 15q23-q26 (MRT27), and 6q26-q27 (MRT28), respectively. Loci ranged between 1.2 and 45.6 Mb in length. One family showed linkage to chromosome 8q24.3, and we identified a mutation in TRAPPC9. Our study further highlights the extreme heterogeneity of NS-ARID, and suggests that no major disease gene is to be expected, at least in this study group. Systematic analysis of large numbers of affected families, as presented here, will help discovering the genetic causes of ID.     

An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29

Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.     

DFNB20: a novel locus for autosomal recessive, non-syndromal sensorineural hearing loss maps to chromosome 11q25-qter

Autosomal recessive non-syndromal deafness is an extremely heterogeneous condition with at least 19 loci (DFNB1-19) already described. We have used autozygosity mapping to localise a further novel locus, DFNB20, to chromosome 11q25-qter in a consanguineous family originating from Pakistan. A region of homozygosity was observed in affected individuals spanning the interval D11S969-qter.     

A locus for asphyxiating thoracic dystrophy,ATD, maps to chromosome 15q13

Asphyxiating thoracic dystrophy (ATD), or Jeune syndrome, is a multisystem autosomal recessive disorder associated with a characteristic skeletal dysplasia and variable renal, hepatic, pancreatic, and retinal abnormalities. We have performed a genome wide linkage search using autozygosity mapping in a cohort of four consanguineous families with ATD, three of which originate from Pakistan, and one from southern Italy. In these families, as well as in a fifth consanguineous family from France, we localised a novel ATD locus (ATD) to chromosome 15q13, with a maximum cumulative two point lod score at D15S1031 (Zmax=3.77 at theta=0.00). Five consanguineous families shared a 1.2 cM region of homozygosity between D15S165 and D15S1010. Investigation of a further four European kindreds, with no known parental consanguinity, showed evidence of marker homozygosity across a similar interval. Families with both mild and severe forms of ATD mapped to 15q13, but mutation analysis of two candidate genes, GREMLIN and FORMIN, did not show pathogenic mutations.     

Exclusion of chromosome 9 helps to identify mild variants of acromesomelic dysplasia Maroteaux type

Acromesomelic dysplasia Maroteaux type (AMDM) is an autosomal recessive disorder belonging to the group of acromesomelic dysplasias. AMDM is characterised by severe dwarfism with shortening of the middle and distal segments of the limbs. An AMDM gene has recently been mapped to human chromosome 9p13-q12 by homozygosity mapping in four consanguineous families. Here, we show linkage of the disease gene to chromosome 9p13-q12 in four of five consanguineous AMDM families and its exclusion in a fifth family with two children affected with a mild form of the disease. This study suggests that genetic heterogeneity accounts for the variable clinical and radiological severity of AMDM.     

Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with non‐syndromic autosomal recessive deafness

Recently the TMPRSS3 gene, which encodes a transmembrane serine protease, was found to be responsible for two non‐syndromic recessive deafness loci located on human chromosome 21q22.3, DFNB8 and DFNB10. We found evidence for linkage to the DFNB8/10 locus in two unrelated consanguineous Tunisian families segregating congenital autosomal recessive sensorineural deafness. The audiometric tests showed a loss of hearing greater than 70 dB, in all affected individuals of both families. Mutation screening of TMPRSS3 revealed two novel missense mutations, W251C and P404L, altering highly conserved amino acids of the serine protease domain. Both mutations were not found in 200 control Tunisian chromosomes. The detection of naturally‐occurring TMPRSS3 missense mutations in deafness families identifies functionally important amino acids. Comparative protein modeling of the TMPRSS3 protease domain predicted that W251C might lead to a structural rearrangement affecting the active site H257 and that P404L might alter the geometry of the active site loop and therefore affect the serine protease activity. Hum Mutat 18:101–108, 2001. © 2001 Wiley‐Liss, Inc.     

Search for genes involved in Joubert syndrome: Evidence that one or more major loci are yet to be identified and exclusion of candidate genes EN1, EN2, FGF8, and BARHL1

Joubert syndrome (JS) is a rare autosomal recessive malformation syndrome involving agenesis or dysgenesis of the cerebellar vermis with accompanying brainstem malformations. JS is further characterized by hypotonia, developmental delay, intermittent hyperpnea, and abnormal eye movements. The biochemical and molecular basis of JS remains unknown, although several genes that are crucial in the development of the cerebellum have been proposed as attractive candidate genes. JS is clinically heterogeneous; this, together with previous linkage analyses, suggests that there may also be genetic heterogeneity. A locus for JS was previously identified on chromosome 9q34 by linkage analysis in a consanguineous family of Arabian origin. A putative second JS locus was recently suggested when a deletion on chromosome 17p11.2 was observed in a patient with Smith‐Magenis syndrome and JS phenotype. We have investigated a cohort of apparently unrelated North American JS pedigrees for association with the loci on chromosomes 9q34 and 17p11.2 and excluded them in all cases where data were informative. Analysis of an additional 21 unrelated JS patients showed no evidence of homozygosity at the 9q34 and 17p11.2 loci that would suggest inheritance of founder JS mutation(s) or unreported consanguinity. Together, these data suggest that one or more major loci for JS remain to be identified. Consequently, we undertook mutation analysis of several functional candidate genes, EN1, EN2, and FGF8, in a total of 26 unrelated JS patients. Our data suggest that all of these genes may be excluded from a direct pathogenic role in JS. The BARHL1 gene, which localizes to chromosome 9q34 and has previously been proposed as a strong positional candidate gene for JS, was also investigated and excluded from involvement in JS that is linked to chromosome 9q34. © 2002 Wiley‐Liss, Inc.     

Targeted scan of fifteen regions for nonsyndromic cleft lip and palate in Filipino families

Cleft lip with or without cleft palate (CL/P) is a congenital anomaly with variable birth prevalence based on geographic origins, with the highest rates commonly found in Asian populations. About 70% of cases are nonsyndromic (NS), in which the affected individual has no other abnormalities. NS CL/P is a complex disorder with genetic and environmental effects and no specific genetic loci yet confirmed. Fifteen candidate regions were examined for linkage to NS CL/P. Regions were chosen based on previous suggestive linkage and/or association in human families, or suggestive animal model data. Polymorphic markers in these regions were genotyped for analysis on 36 Filipino families comprised of 126 affected and 218 unaffected individuals. An additional 70 families with 149 affecteds were used for replication of suggestive results. Parametric (LOD score) and nonparametric (SIMIBD) linkage analyses were performed as well as transmission disequilibrium test (TDT) analysis. Five markers yielded suggestive results from the 36 families. The parametric LOD scores for the MSX1-CA and D4S1629 were >1.0 and the SIMIBD P values for D6S1029 and RFC1 are suggestive (<0.06), while the SIMIBD P value of 0.01 for TGFA was significant. Since the Msx1 mouse knockout has cleft palate and MSX1 mutations have been found in rare cases of syndromic CL/P, this locus is especially plausible for linkage. Previous studies have also found linkage of NS CL/P to 4q31 and 6p23. These regions contain several candidate genes, including AP2 at 6p23 and FGF2, BMPR1B, and MADH1 at 4q31. TGFA has both linkage and linkage disequilibrium data supporting it as a candidate gene for NS CL/P. While no region was definitively confirmed for linkage to NS CL/P, the data do support further investigation using larger sample sizes and candidate gene studies at 2p13.2, 4p16.2, 4q31, 6p23, and 16q22-24.     

Search for genes involved in Joubert syndrome: evidence that one or more major loci are yet to be identified and exclusion of candidate genes EN1, EN2, FGF8, and BARHL1.

Joubert syndrome (JS) is a rare autosomal recessive malformation syndrome involving agenesis or dysgenesis of the cerebellar vermis with accompanying brainstem malformations. JS is further characterized by hypotonia, developmental delay, intermittent hyperpnea, and abnormal eye movements. The biochemical and molecular basis of JS remains unknown, although several genes that are crucial in the development of the cerebellum have been proposed as attractive candidate genes. JS is clinically heterogeneous; this, together with previous linkage analyses, suggests that there may also be genetic heterogeneity. A locus for JS was previously identified on chromosome 9q34 by linkage analysis in a consanguineous family of Arabian origin. A putative second JS locus was recently suggested when a deletion on chromosome 17p11.2 was observed in a patient with Smith-Magenis syndrome and JS phenotype. We have investigated a cohort of apparently unrelated North American JS pedigrees for association with the loci on chromosomes 9q34 and 17p11.2 and excluded them in all cases where data were informative. Analysis of an additional 21 unrelated JS patients showed no evidence of homozygosity at the 9q34 and 17p11.2 loci that would suggest inheritance of founder JS mutation(s) or unreported consanguinity. Together, these data suggest that one or more major loci for JS remain to be identified. Consequently, we undertook mutation analysis of several functional candidate genes, EN1, EN2, and FGF8, in a total of 26 unrelated JS patients. Our data suggest that all of these genes may be excluded from a direct pathogenic role in JS. The BARHL1 gene, which localizes to chromosome 9q34 and has previously been proposed as a strong positional candidate gene for JS, was also investigated and excluded from involvement in JS that is linked to chromosome 9q34.     

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

Homozygosity mapping within consanguineous families is a powerful method of localising genes for autosomal recessive disease. We investigated a family from Punjab, Pakistan, a region where consanguineous marriages are frequent. The parents have no detectable clinical disorders. However, five out of six children present with schizophrenia, epilepsy or hearing impairment either alone or in combination. This unusual phenotype in several offspring of first cousins is strongly suggestive of a rare, Mendelian recessive disorder. Two genome-wide scans initially using low-density microsatellites, and subsequently high-density SNP markers were used to map homozygous-by-descent regions in affected individuals. Candidate genes within these loci were subsequently screened for mutations. Homozygosity analysis and inbreeding coefficients were investigated to give an estimate of consanguinity. Two putative disease loci were mapped to 22q12.3-q13.3 and 2p24.3. The candidate locus on chromosome 2p24 overlaps with a deafness locus, DFNB47, linked to autosomal recessive hearing impairment, while positive findings reported for affective psychosis and schizophrenia cluster in a region of 4-5 cM on 22q13.1 within our second candidate locus. Sequence analysis of three candidate genes (KCNF1 (2p); ATF4, CACNG2 (22q)) did not reveal any exonic mutations. Inbreeding coefficients calculated for each family member support a very high degree of ancestral and recent inbreeding. The screening of other candidate genes located within these newly identified disease intervals on Chr2p24.3 and 22q12.3-q13.3 may lead to the discovery of causative variants, and consequent disrupted molecular pathways associated with this rare phenotype.     

Evidence for the multigenic inheritance of schizophrenia

Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these findings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy‐seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome‐wide significant linkage (Z = 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the α7‐nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z = 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait‐locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci. © 2001 Wiley‐Liss, Inc.     

Familial atopy in Australian pedigrees: adventitious linkage to chromosome 8 is not confirmed nor is there evidence of linkage to the high affinity IgE receptor

Atopy frequently displays autosomal dominant inheritance and recent studies have favoured genetic linkage between atopy and the human chromosome 11q13. We have studied 12 extended families with aggregation of atopy consistent with autosomal dominant inheritance. The families have been studied for linkage of asthma and atopy to loci on chromosome 8p following the observation that one family suggested preliminary evidence of linkage to an anonymous hypervariable locus cloned from a DNA fingerprint and mapped to 8pter-p22. Subsequent analysis shows this putative linkage to be adventitious as the remaining 11 families do not support linkage between atopy and 8p, We have analysed the same families for evidence of linkage of atopy to loci on 11q13. In these families there is no evidence of association between atopy and the 11q loci stronger than that expected by chance alone; furthermore there is no suggestion subpopulation of these families display linkage between atopy and the loci. In addition neither the 8p loci nor the 11q loci exhibit evidence of linkage to atopy by affected sib-pair analysis. This also conflicts with previously published data for 11q.     

A non‐sense MCM9 mutation in a familial case of primary ovarian insufficiency

Primary ovarian insufficiency (POI) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole‐exome sequencing of the two patients and a non‐affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c.1483G>T [p.E495*], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum.     

Genetic analyses supporting colorectal,gastric, and prostate cancer syndromes

Colorectal cancer (CRC), prostate cancer (PrC), and gastric cancer (GC) are common worldwide, and the incidence is to a certain extent dependent on genetics. We have recently shown that in families with more than one case of CRC, the risk of other malignancies is increased. We therefore suggested the presence of not yet described CRC syndromes. In this study, we have searched for genetic susceptibility loci for potential cancer syndromes involving CRC combined with PrC and/or GC. We have performed SNP (single‐nucleotide polymorphism)‐based linkage analyses in 45 families with CRC, PrC, and GC. In the regions with suggested linkage, we performed exome and association haplotype analyses. Five loci generated a high logarithm of odds (HLOD) score >2, suggestive of linkage, in chromosome bands 1q31‐32, 1q24‐25, 6q25‐26, 18p11‐q11, and Xp11. Exome analysis detected no potential pathogenic sequence variants. The haplotype association study showed that one of the top five haplotypes with the lowest P value in the chromosome band 6q25 interestingly was found in the family which contributed the most to the increased HLOD at that locus. This study supports a suggested hereditary cancer syndrome involving CRC and PrC and indicates a location at 6q25. The impact of this locus needs to be confirmed in additional studies.     

An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group

Multiple sclerosis (MS) is a complex trait with a sibling relative risk (lambda(sibs)) between 18 and 36. We report a multistage genome scan of 552 sibling pairs from 442 families, the largest MS family sample assessed for linkage. The first stage consisted of a genome scan for linkage with 498 microsatellite markers at an average spacing of 7 cM in 219 sibling pairs. The second stage involved further genotyping of markers from positive regions in an independent sample of 333 affected sibling pairs. The global distribution of allele sharing for all markers showed a shift towards greater sharing within the affected sibling pair group but not in the discordant sibling pair group. This shift indicates that the number of contributing genetic factors is likely to be moderate to large. Only markers at chromosome 6p showed significant evidence for linkage (MLOD=4.40), while other regions were only suggestive (1p, 2q, 5p, 9q, 11p, 12q, 18p, 18q and 21q) with MLODs greater than 1.0. The replication analysis involving all 552 affected sibling pairs confirmed suggestive evidence for five locations, namely, 2q27 (MLOD=2.27), 5p15 (MLOD=2.09), 18p11 (MLOD=1.68), 9q21 (MLOD=1.58) and 1p31 (MLOD=1.33). Suggestive linkage evidence for a previously reported location on chromosome 17q (MLOD=1.67) and a prior association with marker D17S789 was replicated. We showed that the overall excess allele sharing we observed for the entire sample was due to increased allele sharing within the DRB1*15 negative subgroup alone. This observation is most consistent with a model of genetic heterogeneity between HLA and other genetic loci. These findings offer guidance for future genetic studies including dense SNP linkage disequilibrium analysis.     

Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint

Familial hypomagnesemia with secondary hypocalcemia (HSH) (MIM 307600) was studied in three inbred Bedouin kindreds from Israel. The three kindreds, one extended and two nuclear families, contained 13 affected individuals, 11 males and two females. Assuming that the individuals affected with hypomagnesemia shared a chromosomal region inherited from a common ancestor, we used a DNA pooling strategy in a genome-wide search for loci which show homozygosity for shared alleles in affected individuals. DNA samples from affected individuals within a single kindred were pooled and used as the template for PCR amplification of short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected siblings and parents were used as controls. A shift towards homozygosity was observed in the affected DNA pool compared with the control pools with D9S301 (GATA7D12). Genotyping of individual DNA samples with D9S301 and several flanking markers confirmed linkage to chromosome 9 with maximum LOD scores of 3.4 (theta = 0.05), 3.7 (theta = 0) and 2.3 (theta = 0) for the three families. We have identified a 14 cM interval on chromosome 9 (9q12-9q22.2), flanked by proximal marker D9S1874 and distal marker D9S1807, within which all affected individuals from the three kindreds are homozygous for a shared haplotype. The disease segregates with a common affected haplotype in the three families, suggesting that hypomagnesemia is caused by a common ancestral mutation in these families. Although HSH has been previously reported to be X linked, these linkage data demonstrate that the disorder is an autosomal recessive disease in these kindreds. Mapping of a chromosomal breakpoint in a somatic cell line established from a patient with HSH and a balanced X;9 translocation placed the chromosomal breakpoint in a 500 kb region flanked by D9S1844 and D9S273. Identification of the gene responsible for hypomagnesemia will provide insight into the regulation of this essential cation.      

Chromosome abnormality rate among Iranian patients with idiopathic mental retardation from consanguineous marriages

Introduction

Mental retardation (MR) has heterogeneous aetiology mostly with genetic causes. Chromosomal aberrations are one of the most common causes of MR. Reports on chromosome abnormality rate among consanguineous families are sparse. In order to identify the chromosome abnormality rate in idiopathic mental retardation from consanguineous marriages, a total of 322 Iranian families with positive family history for MR were investigated in the Genetics Research Center.

Material and methods

In the majority of families (92%) at least two sibs were affected with MR and none had specific chromosomal syndromes such as Down syndrome. Standard cytogenetic techniques using high resolution GTG banding were carried out on all the patients.

Results

The overall chromosome abnormality rate contributing to mental retardation was 1.24% (4 cases), which comprised 46,XY,der(18)t(4;18)(q31.1;q23)mat; 45,XY,-21,-22,+der(22)t(21;22)(q21.1;q13.33)mat; 46,XY,rec(2)dup(2p)inv(2)(p25.1q37.3)pat, and 46,XY,der(11)t(10;11)(q25.2;q25)pat.

Conclusions

Although the most likely genetic cause of mental retardation in patients with consanguineous parents is autosomal recessive, the fact that 1.24% of our patients had chromosomal abnormalities emphasizes the importance of cytogenetic investigation as the first laboratory genetic tests for all MR patients. To our knowledge, this is the first report on the rate of chromosome abnormality among patients with idiopathic mental retardation from consanguineous marriages.     

Splice-site mutations in the <Emphasis Type="Italic">TRIC</Emphasis> gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families

Hereditary hearing impairment (HI) displays extensive genetic heterogeneity. To date, 67 autosomal recessive nonsyndromic hearing impairment (ARNSHI) loci have been mapped, and 24 genes have been identified. This report describes three large consanguineous ARNSHI Pakistani families, all of which display linkage to marker loci located in the genetic interval of DFNB49 locus on chromosome 5q13. Recently, Riazuddin et al. (Am J Hum Genet 2006; 79:1040–1051) reported that variants within the TRIC gene, which encodes tricellulin, are responsible for HI due to DFNB49. TRIC gene sequencing in these three families led to the identification of a novel mutation (IVS4 + 1G > A) in one family and the discovery of a previously described mutation (IVS4 + 2T > C) in two families. It is estimated that 1.06% (95% confidence interval 0.02–3.06%) of families with ARNSHI in Pakistan manifest HI due to mutations in the TRIC gene.