ClinVar Genomic variation as it relates to human health

Autism (present) , Asthma (present) , Allergic rhinitis (present) , Attention deficit hyperactivity disorder (present) , Hearing impairment (present) , Delayed speech and language development (present) , Small for gestational age (present) , Diabetes mellitus type 1 (present) , Astigmatism (present) (less)

A mutation consisting of deletion of 1 guanine (G) in a run of 6 guanines extending from position 30 to position 35 in the GJB2 gene has been observed by several groups. Some referred to the deleted nucleotide as 30G (the first of the 6 Gs), whereas others referred to it as 35G. The second mutation found by Carrasquillo et al. (1997) to be responsible for nonsyndromic recessive deafness (DFNB1A; 220290) in a Muslim-Israeli village in the lower Galilee was a deletion of a guanine residue at cDNA position 35 (35delG), causing a frameshift of the coding sequence leading to premature chain termination at the twelfth amino acid. The mutation was on a different haplotype from the W77R mutation (121011.0004). Zelante et al. (1997) found a very high frequency of the 35delG mutation in Spanish, Italian, and Israeli autosomal recessive neurosensory deafness patients, in whom it accounted for approximately 50% of cases. This might be interpreted as evidence for an ancient deletion mutation that had spread in Europe and Middle-East; however, the mutation identified in the inbred group by Carrasquillo et al. (1997) was shown by haplotype analysis to be of recent origin and on different haplotypes from those identified by Zelante et al. (1997). Thus, these mutations are all likely different, independent and recurrent, and arise due to the run of Gs being a mutation hotspot. Haplotype analysis of 35delG mutations in different populations can be used to address this question definitively. Denoyelle et al. (1997) found that the 30delG mutation accounted for approximately 70% of CX26 mutant alleles in a study of 65 Caucasian families with prelingual deafness originating from various countries. The high frequency of this mutation may recommend it for genetic counseling in families with a single deaf child. Denoyelle et al. (1997) made the significant observation that only moderate hearing loss was found in some individuals homozygous for the 30delG mutation. Among 82 families from Italy and Spain with recessive nonsyndromic deafness and 54 unrelated individuals with apparently sporadic congenital deafness, Estivill et al. (1998) found mutations in the GJB2 gene in 49% of participants with recessive deafness and 37% of sporadic cases. The 35delG mutation accounted for 85% of GJB2 mutations, and 6 other mutations accounted for 6% of alleles; no changes in the coding region of GJD2 were detected in 9% of DFNB1 alleles. The carrier frequency of the 35delG mutation in the general population was 1 in 31 (95% CI, 1 in 19 to 1 in 87). Morell et al. (1998) found a prevalence of 0.73% for heterozygosity for the 30delG mutation in Ashkenazi Jews. Audiologic examination of carriers of the mutant allele who had normal hearing showed subtle differences in their otoacoustic emissions, suggesting that the expression of mutations in GJB2 may be semidominant. Reporting from Iowa, Green et al. (1999) found that of 52 sequential probands referred for congenital sensorineural hearing loss, 22 (42%) were found to have GJB2 mutations. They identified the 35delG mutation in 29 of the 41 mutant alleles. Of the probands' sibs, all homozygotes and compound heterozygotes had deafness. They found 35delG heterozygosity in 14 of 560 controls, for a carrier rate of 2.5%. The carrier rate for all recessive deafness-causing GJB2 mutations was determined to be 3.01%. Calculated sensitivity and specificity values for a screening test based on the 35delG mutation alone were 96.9% and 97.4%, respectively, and observed values were 94% and 97%, respectively. Antoniadi et al. (1999) analyzed 395 voluntary healthy Greek blood donors for the 35delG mutation of the GJB2 gene. They detected 14 heterozygotes, giving a carrier frequency of 3.5% in the Greek population. With an incidence of prelingual deafness of about 1 in 1,000 children, homozygosity for the 35delG mutation should account for about 30% of all cases. The discovery of this very common mutation in the most common form of genetic hearing loss should enable easy DNA diagnosis, carrier detection, and prenatal diagnosis. Because of the high frequency of carriers of the 35delG mutation in the Greek population reported by Antoniadi et al. (1999), it is perhaps not surprising that pseudodominant inheritance was observed in 2 families reported by Pampanos et al. (2000). In a study of 35 Japanese families with bilateral sensorineural hearing loss, Abe et al. (2000) found no individuals with this mutation. In addition, they found a high prevalence of a novel frameshift mutation (121011.0014) in these families. Kudo et al. (2000) found no cases of the 30delG allele among 39 Japanese patients with prelingual deafness. Gasparini et al. (2000) analyzed the 35delG mutation in 3,270 random controls from 17 European countries. They detected a carrier frequency of 1 in 35 in southern Europe and 1 in 79 in central and northern Europe. In addition, 35delG was detected in 5 of 376 Jewish subjects of different origins, but was absent in other non-European populations. In a study of 560 persons from 5 ethnic groups of Russia, Anichkina et al. (2001) found the 35delG mutation in 12 chromosomes, giving a carrier frequency of 1 in 47. These results demonstrated that the 35delG mutation is present not only in western but also in eastern European (Finno-Ugric and Turkic) populations. In a study of 76 Austrian patients with sensorineural hearing loss, Loffler et al. (2001) found that the 35delG mutation accounted for 65.4% of GJB2 mutant alleles among 13 patients with biallelic GJB2 mutations. A 35delG carrier frequency of 1 in 112 (0.9%) was observed among 672 blood donors from Tirol (West-Austria). Van Laer et al. (2001) studied 35 Belgian, 30 British, and 49 American patients with nonsyndromic hearing impairment who were homozygous for the 35delG mutation and 70 Belgian, 30 British, and 50 American normal hearing controls. Four single-nucleotide polymorphisms mapped in the immediate vicinity of the GJB2 gene, and 2 positioned some distance from it were analyzed. Significant differences between the genotypes of patients and controls for the 5 SNPs closest to the GJB2 gene were found, with nearly complete association of 1 SNP allele with the 35delG mutation. Van Laer et al. (2001) concluded that the 35delG mutation is derived from a common, albeit ancient, founder. Oliveira et al. (2002) added Brazil to the countries in which the 35delG mutation is a frequent cause of deafness. In a study in Italy of 179 patients with hearing loss, Gualandi et al. (2002) found that the 35delG mutation accounted for 22.1% of analyzed chromosomes in sporadic cases and 39.4% in familial cases; 35delG prevalence reached 41% in autosomal recessive and 44.4% in pseudodominant pedigrees. In a high proportion of 35delG heterozygous hearing loss patients (52%), no second GJB2 mutation was detected. D'Andrea et al. (2002) showed that the 35delG mutation, which they identified in almost 90% of an affected Italian population, resulted in no CX26 expression following transient transfection in HeLa cells. Furthermore, there was no dye transfer between clusters of cells expressing this mutation. De Brouwer et al. (2003) performed a genetic analysis of a large consanguineous family that was previously described by Marres and Cremers (1989). Patients in 1 branch of the family were homozygous for the 35delG mutation in the GJB2 gene, whereas patients in 2 other branches carried mutations in the CDH23 gene (605516.0008-605516.0009) causing DFNB12 (601386). Del Castillo et al. (2002) reported 2 Spanish individuals with severe hearing loss who were found to be compound heterozygous for the 35delG mutation and a 309-kb deletion in the GJB6 gene (604418.0004), consistent with digenic inheritance (see 220290). The GJB6 deletion truncating the GJB6 gene was shown to be the accompanying mutation in approximately 50% of deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain. Rothrock et al. (2003) presented evidence that the 35delG mutation arose in European and Middle Eastern populations from a single mutational event on a founder chromosome. They felt that the high frequency does not represent a mutation hotspot. They found the same, relatively rare, polymorphism associated with the 35delG mutation immediately upstream of the first exon of GJB2 in all populations studied including those in Italy, Brazil, and North America. Salvinelli et al. (2003) reported a low frequency of the 35delG mutation in Sicilians with hearing loss, whereas it had previously been reported to be responsible for most nonsyndromic recessive deafness in American and European populations. Only 5 of 53 probands with familial deafness were homozygous for 35delG; another 5 were heterozygous for 35delG and 2 more were compound heterozygous for 35delG and 167delT (121011.0010). Lucotte and Pinna (2003) reported a frequency of 35delG heterozygotes of 3.35% in Corsica. This value was lower than that in continental Italy but similar to values reported for Sardinia and for Greece. Alvarez et al. (2005) screened the GJB2 gene in 34 Spanish Romani (gypsy) families with autosomal recessive nonsyndromic hearing loss and found mutations in 50%. The predominant allele was W24X (121011.0003), accounting for 79% of DFNB1 alleles; 35delG was the second most common allele (17%). Wilch et al. (2006) described a large kindred of German descent in which they found a novel allele of the GJB2 gene that segregated with deafness when present in trans with the 35delG allele of GJB2. Qualitative PCR-based allele-specific expression assays showed that expression of both GJB2 and GJB6 from the novel allele was dramatically reduced. The findings suggested possible coregulation of GJB2 and GJB6, which are closely situated on 13q. The DFNB1 locus (220290) encompasses GJB2 and GJB6. The 2 genes lie within 30 kb of each other and their products are coexpressed in the cochlea. Wilch et al. (2010) reported follow-up of the family reported by Wilch et al. (2006) in which 4 deaf individuals were heterozygous for the 35delG allele. Array CGH of these patients identified a common 131.4-kb deletion on chromosome 13 that was carried in trans with the 35delG mutation. The deletion was not found in 160 control individuals or in 528 patients with hearing loss and a heterozygous GJB2 or GJB6 mutation. The proximal breakpoint of the deletion lies more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6, leaving both of those genes intact. Wilch et al. (2010) suggested that the deleted region contains a distant cis-regulatory region that controls GJB2 and GJB6 expression. Lezirovitz et al. (2006) identified a homozygous 35delG mutation in the GJB2 gene in 2 Brazilian sibs with profound congenital sensorineural deafness. A third sib with a milder form of progressive hearing loss beginning in childhood was also homozygous for the mutation, suggesting phenotypic variability. One of the sibs with profound deafness also had oculocutaneous albinism type IV (OCA4; 606574) caused by a homozygous mutation in the MATP gene (606202.0009). Lezirovitz et al. (2006) concluded that congenital deafness and oculocutaneous albinism due to mutations in 2 different genes as seen in their Brazilian family suggested a similar coincident inheritance of 2 separate recessive disorders in the Sephardic family reported by Ziprkowski and Adam (1964) (see 220900). By haplotype analysis of 60 unrelated Greek individuals homozygous for the 35delG mutation and 60 Greek hearing controls, Kokotas et al. (2008) found evidence that the mutation was due to a common founder effect. The mutation was estimated to have occurred about 700 generations or approximately 14,000 years ago. Hilgert et al. (2009) noted that the hearing loss associated with homozygosity for the 35delG mutation shows marked phenotypic variability, ranging from mild to profound. A genomewide association study of 255 individuals homozygous for 35delG, followed by a replication study of 297 samples, yielded 9 SNPs that showed significant association with mild/moderate hearing loss compared to profound hearing loss (p values between 3 x 10(-3) and 1 x 10(-4)). Although these SNPs may reflect a small modifying effect on the phenotype, Hilgert et al. (2009) concluded that the overall results suggested that the phenotypic variability in this subset of patients cannot be explained by the effect of 1 major modifier gene. Ammar-Khodja et al. (2009) found that the 35delG mutation was the most common mutant allele in deaf individuals in Algeria, representing 76% of mutant alleles at the DFNB1 locus identified in 25 families. Fifteen families with nonsyndromic deafness were homozygous for this mutation, 2 were compound heterozygous for 35delG and another pathogenic mutation in the GJB2 gene, and 3 were heterozygous for the 35delG mutation. One patient who was heterozygous for the mutation was found to have Usher syndrome (276900) due to a homozygous mutation in the MYO7A gene (276903). Among 1,510 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 54 heterozygotes and no homozygotes for the 35delG mutation in the GJB2 gene, for a frequency of 0.036, or 1 in 28. The population frequency of this allele in other populations is about 1 in 40 (Kenneson et al., 2002). (less)

A mutation consisting of deletion of 1 guanine (G) in a run of 6 guanines extending from position 30 to position 35 in the GJB2 gene has been observed by several groups. Some referred to the deleted nucleotide as 30G (the first of the 6 Gs), whereas others referred to it as 35G. The second mutation found by Carrasquillo et al. (1997) to be responsible for nonsyndromic recessive deafness (DFNB1A; 220290) in a Muslim-Israeli village in the lower Galilee was a deletion of a guanine residue at cDNA position 35 (35delG), causing a frameshift of the coding sequence leading to premature chain termination at the twelfth amino acid. The mutation was on a different haplotype from the W77R mutation (121011.0004). Zelante et al. (1997) found a very high frequency of the 35delG mutation in Spanish, Italian, and Israeli autosomal recessive neurosensory deafness patients, in whom it accounted for approximately 50% of cases. This might be interpreted as evidence for an ancient deletion mutation that had spread in Europe and Middle-East; however, the mutation identified in the inbred group by Carrasquillo et al. (1997) was shown by haplotype analysis to be of recent origin and on different haplotypes from those identified by Zelante et al. (1997). Thus, these mutations are all likely different, independent and recurrent, and arise due to the run of Gs being a mutation hotspot. Haplotype analysis of 35delG mutations in different populations can be used to address this question definitively. Denoyelle et al. (1997) found that the 30delG mutation accounted for approximately 70% of CX26 mutant alleles in a study of 65 Caucasian families with prelingual deafness originating from various countries. The high frequency of this mutation may recommend it for genetic counseling in families with a single deaf child. Denoyelle et al. (1997) made the significant observation that only moderate hearing loss was found in some individuals homozygous for the 30delG mutation. Among 82 families from Italy and Spain with recessive nonsyndromic deafness and 54 unrelated individuals with apparently sporadic congenital deafness, Estivill et al. (1998) found mutations in the GJB2 gene in 49% of participants with recessive deafness and 37% of sporadic cases. The 35delG mutation accounted for 85% of GJB2 mutations, and 6 other mutations accounted for 6% of alleles; no changes in the coding region of GJD2 were detected in 9% of DFNB1 alleles. The carrier frequency of the 35delG mutation in the general population was 1 in 31 (95% CI, 1 in 19 to 1 in 87). Morell et al. (1998) found a prevalence of 0.73% for heterozygosity for the 30delG mutation in Ashkenazi Jews. Audiologic examination of carriers of the mutant allele who had normal hearing showed subtle differences in their otoacoustic emissions, suggesting that the expression of mutations in GJB2 may be semidominant. Reporting from Iowa, Green et al. (1999) found that of 52 sequential probands referred for congenital sensorineural hearing loss, 22 (42%) were found to have GJB2 mutations. They identified the 35delG mutation in 29 of the 41 mutant alleles. Of the probands' sibs, all homozygotes and compound heterozygotes had deafness. They found 35delG heterozygosity in 14 of 560 controls, for a carrier rate of 2.5%. The carrier rate for all recessive deafness-causing GJB2 mutations was determined to be 3.01%. Calculated sensitivity and specificity values for a screening test based on the 35delG mutation alone were 96.9% and 97.4%, respectively, and observed values were 94% and 97%, respectively. Antoniadi et al. (1999) analyzed 395 voluntary healthy Greek blood donors for the 35delG mutation of the GJB2 gene. They detected 14 heterozygotes, giving a carrier frequency of 3.5% in the Greek population. With an incidence of prelingual deafness of about 1 in 1,000 children, homozygosity for the 35delG mutation should account for about 30% of all cases. The discovery of this very common mutation in the most common form of genetic hearing loss should enable easy DNA diagnosis, carrier detection, and prenatal diagnosis. Because of the high frequency of carriers of the 35delG mutation in the Greek population reported by Antoniadi et al. (1999), it is perhaps not surprising that pseudodominant inheritance was observed in 2 families reported by Pampanos et al. (2000). In a study of 35 Japanese families with bilateral sensorineural hearing loss, Abe et al. (2000) found no individuals with this mutation. In addition, they found a high prevalence of a novel frameshift mutation (121011.0014) in these families. Kudo et al. (2000) found no cases of the 30delG allele among 39 Japanese patients with prelingual deafness. Gasparini et al. (2000) analyzed the 35delG mutation in 3,270 random controls from 17 European countries. They detected a carrier frequency of 1 in 35 in southern Europe and 1 in 79 in central and northern Europe. In addition, 35delG was detected in 5 of 376 Jewish subjects of different origins, but was absent in other non-European populations. In a study of 560 persons from 5 ethnic groups of Russia, Anichkina et al. (2001) found the 35delG mutation in 12 chromosomes, giving a carrier frequency of 1 in 47. These results demonstrated that the 35delG mutation is present not only in western but also in eastern European (Finno-Ugric and Turkic) populations. In a study of 76 Austrian patients with sensorineural hearing loss, Loffler et al. (2001) found that the 35delG mutation accounted for 65.4% of GJB2 mutant alleles among 13 patients with biallelic GJB2 mutations. A 35delG carrier frequency of 1 in 112 (0.9%) was observed among 672 blood donors from Tirol (West-Austria). Van Laer et al. (2001) studied 35 Belgian, 30 British, and 49 American patients with nonsyndromic hearing impairment who were homozygous for the 35delG mutation and 70 Belgian, 30 British, and 50 American normal hearing controls. Four single-nucleotide polymorphisms mapped in the immediate vicinity of the GJB2 gene, and 2 positioned some distance from it were analyzed. Significant differences between the genotypes of patients and controls for the 5 SNPs closest to the GJB2 gene were found, with nearly complete association of 1 SNP allele with the 35delG mutation. Van Laer et al. (2001) concluded that the 35delG mutation is derived from a common, albeit ancient, founder. Oliveira et al. (2002) added Brazil to the countries in which the 35delG mutation is a frequent cause of deafness. In a study in Italy of 179 patients with hearing loss, Gualandi et al. (2002) found that the 35delG mutation accounted for 22.1% of analyzed chromosomes in sporadic cases and 39.4% in familial cases; 35delG prevalence reached 41% in autosomal recessive and 44.4% in pseudodominant pedigrees. In a high proportion of 35delG heterozygous hearing loss patients (52%), no second GJB2 mutation was detected. D'Andrea et al. (2002) showed that the 35delG mutation, which they identified in almost 90% of an affected Italian population, resulted in no CX26 expression following transient transfection in HeLa cells. Furthermore, there was no dye transfer between clusters of cells expressing this mutation. De Brouwer et al. (2003) performed a genetic analysis of a large consanguineous family that was previously described by Marres and Cremers (1989). Patients in 1 branch of the family were homozygous for the 35delG mutation in the GJB2 gene, whereas patients in 2 other branches carried mutations in the CDH23 gene (605516.0008-605516.0009) causing DFNB12 (601386). Del Castillo et al. (2002) reported 2 Spanish individuals with severe hearing loss who were found to be compound heterozygous for the 35delG mutation and a 309-kb deletion in the GJB6 gene (604418.0004), consistent with digenic inheritance (see 220290). The GJB6 deletion truncating the GJB6 gene was shown to be the accompanying mutation in approximately 50% of deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain. Rothrock et al. (2003) presented evidence that the 35delG mutation arose in European and Middle Eastern populations from a single mutational event on a founder chromosome. They felt that the high frequency does not represent a mutation hotspot. They found the same, relatively rare, polymorphism associated with the 35delG mutation immediately upstream of the first exon of GJB2 in all populations studied including those in Italy, Brazil, and North America. Salvinelli et al. (2003) reported a low frequency of the 35delG mutation in Sicilians with hearing loss, whereas it had previously been reported to be responsible for most nonsyndromic recessive deafness in American and European populations. Only 5 of 53 probands with familial deafness were homozygous for 35delG; another 5 were heterozygous for 35delG and 2 more were compound heterozygous for 35delG and 167delT (121011.0010). Lucotte and Pinna (2003) reported a frequency of 35delG heterozygotes of 3.35% in Corsica. This value was lower than that in continental Italy but similar to values reported for Sardinia and for Greece. Alvarez et al. (2005) screened the GJB2 gene in 34 Spanish Romani (gypsy) families with autosomal recessive nonsyndromic hearing loss and found mutations in 50%. The predominant allele was W24X (121011.0003), accounting for 79% of DFNB1 alleles; 35delG was the second most common allele (17%). Wilch et al. (2006) described a large kindred of German descent in which they found a novel allele of the GJB2 gene that segregated with deafness when present in trans with the 35delG allele of GJB2. Qualitative PCR-based allele-specific expression assays showed that expression of both GJB2 and GJB6 from the novel allele was dramatically reduced. The findings suggested possible coregulation of GJB2 and GJB6, which are closely situated on 13q. The DFNB1 locus (220290) encompasses GJB2 and GJB6. The 2 genes lie within 30 kb of each other and their products are coexpressed in the cochlea. Wilch et al. (2010) reported follow-up of the family reported by Wilch et al. (2006) in which 4 deaf individuals were heterozygous for the 35delG allele. Array CGH of these patients identified a common 131.4-kb deletion on chromosome 13 that was carried in trans with the 35delG mutation. The deletion was not found in 160 control individuals or in 528 patients with hearing loss and a heterozygous GJB2 or GJB6 mutation. The proximal breakpoint of the deletion lies more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6, leaving both of those genes intact. Wilch et al. (2010) suggested that the deleted region contains a distant cis-regulatory region that controls GJB2 and GJB6 expression. Lezirovitz et al. (2006) identified a homozygous 35delG mutation in the GJB2 gene in 2 Brazilian sibs with profound congenital sensorineural deafness. A third sib with a milder form of progressive hearing loss beginning in childhood was also homozygous for the mutation, suggesting phenotypic variability. One of the sibs with profound deafness also had oculocutaneous albinism type IV (OCA4; 606574) caused by a homozygous mutation in the MATP gene (606202.0009). Lezirovitz et al. (2006) concluded that congenital deafness and oculocutaneous albinism due to mutations in 2 different genes as seen in their Brazilian family suggested a similar coincident inheritance of 2 separate recessive disorders in the Sephardic family reported by Ziprkowski and Adam (1964) (see 220900). By haplotype analysis of 60 unrelated Greek individuals homozygous for the 35delG mutation and 60 Greek hearing controls, Kokotas et al. (2008) found evidence that the mutation was due to a common founder effect. The mutation was estimated to have occurred about 700 generations or approximately 14,000 years ago. Hilgert et al. (2009) noted that the hearing loss associated with homozygosity for the 35delG mutation shows marked phenotypic variability, ranging from mild to profound. A genomewide association study of 255 individuals homozygous for 35delG, followed by a replication study of 297 samples, yielded 9 SNPs that showed significant association with mild/moderate hearing loss compared to profound hearing loss (p values between 3 x 10(-3) and 1 x 10(-4)). Although these SNPs may reflect a small modifying effect on the phenotype, Hilgert et al. (2009) concluded that the overall results suggested that the phenotypic variability in this subset of patients cannot be explained by the effect of 1 major modifier gene. Ammar-Khodja et al. (2009) found that the 35delG mutation was the most common mutant allele in deaf individuals in Algeria, representing 76% of mutant alleles at the DFNB1 locus identified in 25 families. Fifteen families with nonsyndromic deafness were homozygous for this mutation, 2 were compound heterozygous for 35delG and another pathogenic mutation in the GJB2 gene, and 3 were heterozygous for the 35delG mutation. One patient who was heterozygous for the mutation was found to have Usher syndrome (276900) due to a homozygous mutation in the MYO7A gene (276903). Among 1,510 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 54 heterozygotes and no homozygotes for the 35delG mutation in the GJB2 gene, for a frequency of 0.036, or 1 in 28. The population frequency of this allele in other populations is about 1 in 40 (Kenneson et al., 2002). (less)