Familial dysautonomia: detection of the IKBKAP IVS20(+6T --> C) and R696P mutations and frequencies among Ashkenazi Jews

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish (AJ) population. Mutations in the IkappaB kinase complex-associated protein (IKBKAP) gene cause FD. Two IKBKAP mutations, IVS20(+6T --> C) and R696P, have been identified in FD patients of AJ descent. The splice site mutation IVS20(+6T --> C) is responsible for > 99.5% of known AJ patients with FD, and haplotype analyses were consistent with a common founder. In contrast, the R696P mutation has been identified in only a few AJ patients. To facilitate carrier detection, a single PCR and allele-specific oligonucleotide (ASO) hybridization assay was developed to facilitate the detection of both the IVS20(+6T --> C) and R696P mutations. Screening of 2,518 anonymous AJ individuals from the New York metropolitan area revealed a carrier frequency for IVS20(+6T --> C) of 1 in 32 (3.2%; 95% CI, 2.5-3.9%), similar to the previously estimated carrier frequency (3.3%) based on disease incidence. No carrier was identified for the R696P lesion, indicating that the mutation was rare in this population (< 1 in 2,500). This sensitive and specific assay should facilitate carrier screening for FD mutations in the AJ community, as well as postnatal diagnostic testing.     

DHCR7 genotypes of cousins with Smith‐Lemli‐Opitz syndrome

Smith‐Lemli‐Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 7‐dehydrocholesterol reductase gene (DHCR7). We report on three cousins with SLOS, all of whom were found to be compound heterozygotes for the common splice site mutation IVS8‐1G→C and the missense mutation T289I. DNA analysis of one set of parents demonstrated that the father carried the missense mutation and the mother carried the IVS8–1G→C mutation. By extension, the two unrelated mothers were both heterozygous for IVS8‐1G→C. This finding supports the notion of a high carrier frequency of the IVS8‐1G→C null mutation in Northern European Caucasians. © 2001 Wiley‐Liss, Inc.     

Haplotype analysis of 94 cystic fibrosis mutations with seven polymorphic CFTR DNA markers

We have analyzed 416 normal and 467 chromosomes carrying 94 different cystic fibrosis (CF) mutations with polymorphic genetic markers J44, IVS6aGATT, IVS8CA, T854, IVS17BTA, IVS17BCA, and TUB20. The number of mutations found with each haplotype is proportional to its frequency among normal chromosomes, suggesting that there is no preferential haplotype in which mutations arise and thus excluding possible selection for specific haplotypes. While many common mutations in the worldwide CF population showed absence of haplotype variation, indicating their recent origins, some mutations were associated with more than one haplotype. The most common CF mutations, ΔF508, G542X, and N1303K, showed the highest number of slippage events at microsatellites, suggesting that they are the most ancient CF mutations. Recurrence was probably the case for 9 CF mutations (R117H, H199Y, R347YH, R347P, L558S, 2184insA, 3272-26A → G, R1162X, and 3849 + 10kbC → T). This analysis of 94 CF mutations should facilitate mutation screening and provides useful data for studies on population genetics of CF. © 1996 Wiley-Liss, Inc.     

Balearic archipelago: three islands,three beta‐thalassemia population patterns

López‐Escribano H, Parera MM, Guix P, Serra JM, Gutierrez A, Balsells D, Oliva‐Berini E, Castro JA, Ramon MM, Picornell A. Balearic archipelago: three islands, three beta‐thalassemia population patterns. The mutation spectrum of 175 β‐thalassemia (β‐thal) carriers, identified in pilot carrier screening on 22,713 individuals from Balearic Islands (Spain), is reported. The β⁰ CD39 (C>T) mutation is the most frequent (61.1%), followed by β⁺ IVS‐I‐110 (G>A) (12.0%), β⁺ IVS‐I‐6 (T>C) and β⁰ IVS‐1‐1 (G>A) (3.4% both) and eight other rare mutations (2.9–0.6%); with a distinct prevalence and distribution between islands. Minorca shows the highest prevalence in Iberian populations, with a single mutation, CD39 (C>T), present in most β‐thal carriers. Ibiza is the only Western Mediterranean population where the most frequent β‐thal mutation is IVS‐I‐110 (G>A). These results can be explained by a combination of historical–demographic characteristics together with evolutionary forces such as founder effect, genetic drift and probably selection by malaria. Knowledge of the mutational spectrum in the Balearic Islands will enable to optimize mutation detection strategy for genetic diagnosis of β‐thal in these islands.     

Molecular analysis and clinical findings in the Spanish Gaucher disease population: Putative haplotype of the N370S ancestral chromosome

Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the lysosomal β-glucocerebrosidase (GBA) gene. As the disease is particularly prevalent among Ashkenazi Jews, most studies have been carried out on this ethnic group. In the current study, we present a mutation analysis of the GBA gene in Spanish patients together with the clinical findings. We conducted a systematic analysis in 53 unrelated GD patients. The GBA gene was initially scanned for nine previously described mutations by ASO hybridization or restriction analysis after PCR amplification. The remaining unidentified alleles were screened by nonisotopic PCR-SSCP analysis and sequenced. This approach allowed the identification of 101 of 106 GD alleles (95.3%) involving 24 different mutations, 11 of which are described for the first time: G113E (455G→A), T134P (517A→C), G389E (1283G→A), P391L (1289C→T), N392I (1292A→T), Y412H (1351T→G), W(-4)X (108G→A), Q169X (662C→T), R257X (886C→T), 500insT, and IVS5+1G→T. Most mutations are present in one or few GD chromosomes. However, two mutations, N370S (1226A→G) and L444P (1448T→C), are very frequent and account for 66.1% of the total number of alleles. Linkage disequilibrium was detected between these two mutations and an intragenic polymorphism, indicating that expansion of founder alleles occurred in both cases. Analysis of several microsatellite markers close to the GBA gene allowed us to establish the putative haplotype of the ancestral N370S chromosome. Hum Mutat 11:295–305, 1998. © 1998 Wiley-Liss, Inc.     

Novel mutations and polymorphisms in the Fanconi anemia group C gene

Fanconi anemia (FA) is an autosomal recessive disorder associated with hypersensitivity to DNA cross-linking agents and bone marrow failure. At least four complementation groups have been defined, and the FA group C gene (FAC) has been cloned. We have screened 76 unrelated FA patients of diverse ethnic and geographic origins and from unknown complementation groups for mutations in the FAC gene either by chemical cleavage mismatch analysis or by single-strand conformational polymorphism (SSCP). Five mutations were detected in four patients (5.3%), including two novel mutations (W22X and L496R). Nine polymorphisms were detected, seven of which have not been described previously (663A → G, L190F, IVS6 + 30C → T, 1312V, V449M, Q465R, and 1974G → A). Six of the nine polymorphisms occurred in patients or controls from the Tswana or Sotho chiefdoms of South Africa and were not found in 50 unrelated European controls. Restriction site assays were established for all 8 pathogenic mutations identified in the FAC gene to date and used to screen a total of 94 unrelated FA patients. This identified only one other group C patient, who was homozygous for the mutation IVS4 + 4A → T. This study indicates that the proportion of FA patients from complementation group C is generally likely to be less than 10%. Guidelines for the selection of FA patients for FAC mutation screening are proposed. © 1996 Wiley-Liss, Inc.     

Identification of the first non-Jewish mutation in familial Dysautonomia

Familial Dysautonomia is an autosomal recessive disease with a remarkably high carrier frequency in the Ashkenazi Jewish population. It has recently been estimated that as many as 1 in 27 Ashkenazi Jews is a carrier of FD. The FD gene has been identified as IKBKAP, and two disease-causing mutations have been identified. The most common mutation, which is present on 99.5% of all FD chromosomes, is an intronic splice site mutation that results in tissue-specific skipping of exon 20. The second mutation, R696P, is a missense mutation that has been identified in 4 unrelated patients heterozygous for the major splice mutation. Interestingly, despite the fact that FD is a recessive disease, normal mRNA and protein are expressed in patient cells. To date, the diagnosis of FD has been limited to individuals of Ashkenazi Jewish descent and identification of the gene has led to widespread diagnostic and carrier testing in this population. In this report, we describe the first non-Jewish IKBKAP mutation, a proline to leucine missense mutation in exon 26, P914L. This mutation is of particular significance because it was identified in a patient who lacks one of the cardinal diagnostic criteria for the disease-pure Ashkenazi Jewish ancestry. In light of this fact, the diagnostic criteria for FD must be expanded. Furthermore, in order to ensure carrier identification in all ethnicities, this mutation must now be considered when screening for FD.     

Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: Haplotype and genotype–phenotype correlation studies in spanish metachromatic leukodystrophy patients

Arylsulfatase A (ARSA) deficiency is the main cause of metachromatic leukodystrophy (MLD), a lysosomal disorder with no specific treatment. In view of the importance of genetic counseling, analyses of mutations and polymorphisms, including the ARSA pseudodeficiency allele, were carried out in 18 unrelated Spanish MLD patients. A systematic search allowed us to identify 100% of the alleles involving 17 different mutations, 12 of which are novel: G32S, L68P, R84W, P94A, G99V, P136S, W193X, H227Y, R288H, G308D, T327I, and IVS6‐12C→G. Two new polymorphisms, 2033C>T and 2059C>T, were identified in intron 6 which, in combination with two polymorphisms previously described (2161C>G and 2213C>G), gave rise to four different haplotypes in the control population. In addition, we also studied polymorphism 842G>T. Linkage disequilibrium was detected between mutations IVS2+1G→A, D255H, and T327I and specific haplotypes, suggesting a unique origin for these mutations. Moreover, mutation T327I was always associated with the T allele of the new rare variant A210A (893C>T). The distribution of mutation D255H (frequency 19.4%) among patients with different MLD clinical presentation revealed a clear genotype–phenotype correlation paralleling that reported for mutation IVS2+1G→A (frequency 25%). Among the novel mutations, only P136S and R288H occurred on a background of the ARSA pseudodeficiency allele. Screening 182 normal chromosomes identified a frequency of 8.8% of this allele; moreover, we identified two unrelated subjects with the polyA‐ mutation in the absence of the N350S mutation, and this infrequent haplotype reinforced the heterogeneity of conditions with ARSA deficiency. Hum Mutat 14:240–248, 1999. © 1999 Wiley‐Liss, Inc.     

Smith‐Lemli‐Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8‐1G→C genotype

Smith‐Lemli‐Opitz syndrome (RHS) (SLOS, OMIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3β‐hydroxysterol Δ⁷‐Δ⁸‐reductase gene, DHCR7. We report a fetus with holoprosencephaly and multiple congenital anomalies who was homozygous for the IVS8‐1G→C mutation. Following termination of pregnancy, both the elevated amniotic fluid 7‐dehydrocholesterol level and the DHCR7 mutations were demonstrated. Two other newborn infants with IVS8‐1G→C/IVS8‐1G→C genotype are described. This report illustrates a severe phenotypic extreme of SLOS associated with a null genotype, underscores the complex relationship between SLOS and holoprosencephaly, and discusses the possible pathogenetic mechanisms of the development of holoprosencephaly in SLOS. © 2001 Wiley‐Liss, Inc.     

Mutation analysis and description of sixteen RSH/Smith‐Lemli‐Opitz syndrome patients: Polymerase chain reaction–based assays to simplify genotyping

We report the clinical and molecular data of 16 patients with RSH/Smith‐Lemli‐Opitz syndrome (RSH/SLOS) with varying phenotypic severity, for which we have identified mutations in both alleles. RSH/SLOS is an autosomal recessive malformation syndrome caused by mutations in the gene encoding the sterol Δ⁷‐reductase. This protein catalyzes the reduction of 7‐dehydrocholesterol to cholesterol in the last step of cholesterol biosynthesis via the Kandutsch‐Russell pathway. In addition to previously reported mutations (T93M, L109P, G147D, W151X, T154M, R242C, A247V, T289I, IVS8‐1G→C, Y408H, and E448K), we have identified six previously undescribed mutations (321G→C, W177R, R242H, Y318N, L341P, and C444Y). We also report rapid polymerase chain reaction (PCR)–based assays developed to detect four of the recurring mutations (T93M, W151X, V326L, and R404C) and six other RSH/SLOS mutations (321G→C, L109P, T154M, T289I, Y318N, and L341P). The purpose of this article is to correlate detailed clinical information with molecular data in order to improve our understanding of the genotype–phenotype correlation of RSH/SLOS and to report the development of PCR‐based assays that will allow more rapid mutation analysis. Am. J. Med. Genet. 94:214–227, 2000. Published 2000 Wiley‐Liss, Inc.     

Tay-Sachs disease and HEXA mutations among Moroccan Jews

Moroccan Jewry (N>750,000) is the only non-Ashkenazi Jewish community in which Tay-Sachs disease (TSD) is not extremely rare. Previous studies among Moroccan Jewish TSD families identified three HEXA mutations. In this study, extended to enzyme-defined and new obilgate TSD carriers, we found four additional mutations. One of them is a novel, IVS5-2(A→G) substitution, resulting in exon skipping, and it was found only among enzyme-defined carriers. The seven HEXA identified mutations among Moroccan Jews are: ΔF^304/305, R170Q, IVS-2(A→G), Y180X, E482K, 1278+TATC, and IVS12+1(G→C). Their respective distribution among 51 unrelated enzyme-defined and obligate carriers is 22:19:6:1:1:1:1. The mutation(s) remain unknown in only three enzyme-defined carriers. Five of the seven Moroccan mutations, including the three most common ones, were not found among Ashkenazi Jews. Compared with the much larger and relatively homogeneous Ashkenazi population, the finding among Moroccan Jews probably reflects their much longer history. Hum Mutat 10:295–300, 1997. © 1997 Wiley-Liss, Inc.     

Detection of a common mutation in the RSH or Smith‐Lemli‐Opitz syndrome by a PCR‐RFLP assay: IVS8‐1G → C is found in over sixty percent of US propositi

The RSH or Smith‐Lemli‐Opitz syndrome (SLOS) is a relatively common autosomal recessive disorder of cholesterol biosynthesis resulting from a deficiency of the enzyme 7‐dehydrocholesterol Δ7‐reductase (7‐DHCR). Mutations in 7‐DHCR gene cause SLOS. Among these, a G → C transversion in the splice acceptor site of exon 9 (IVS8‐1G → C) was suspected to be a frequent mutation, having been detected in about 18% of SLOS patients so far. This mutation results in the elimination of a AIwN1 restriction endonuclease site. We report a simple PCR‐RFLP assay to detect the IVS8‐1 G → C mutation. Using this method, we identified the IVS8‐1G → C mutation in 21 of 33 SLOS propositi. This mutation was detected in one of 90 normal adult Caucasian Americans; but not among 121 Africans from Sierra Leone, 120 Caucasians from Finland, 95 Chinese or 103 Japanese adults. The results of this study provide further evidence that IVS8‐1G → C transversion is a very common mutation in SLOS patients from the US and that the carrier rate in US caucasians may be high. The simple PCR‐RFLP assay developed makes identification of this mutation convenient for diagnosis and for carrier detection. Am. J. Med. Genet. 90:347–350, 2000 © 2000 Wiley‐Liss, Inc.     

A comprehensive study of phenylalanine hydroxylase gene mutations in the Iranian phenylketonuria patients

Phenylketonuria (PKU) is a metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. After thalassemia, PKU is considered as the most common autosomal recessive diseases in the Iranian population. Therefore, an efficient diagnostic strategy is required to identify disease-causing mutations in this population. Following our first report in 2003, here we presented a comprehensive study on the mutation spectrum of the PAH gene in the Iranian population. This study was performed on 280 unrelated chromosomes from 140 Iranian patients with classic PKU. All 13 exons as well as exon-intron boundaries of the PAH gene were analyzed by direct DNA sequencing. Thirty four different mutations were identified by a mutation detection rate of 100%. IVS10-11G > A, p.P281L, R261Q, p.F39del and IVS11+1G > C were the most prevalent mutations with frequencies of 26.07%, 19.3%, 12.86%, 6.07 and 3.93%, respectively. All other mutations represented a relative frequency less than 3.5%. The data from this study provided a comprehensive spectrum of the PAH gene mutations which can facilitate carrier detection and prenatal diagnosis of PKU disease in the Iranian population.     

High Frequency of Mutations in the PIK3CA Gene Helical and Kinase Coding Regions in a Group of Iranian Patients with High-Grade Glioblastomas: Five Novel Mutations

Abstract: Glioblastoma multiform (GBM; World Health Organization (WHO) grade IV) and anaplastic astrocytomas (AA; WHO grade III) are highly aggressive and lethal astrocytic brain tumors. To detect cancer-specific somatic mutations in two hot-spot regions of PIK3CA gene, the helical and kinase domains (encoded by exons 9 and 20, respectively) in GBM and AA, the authors examined the respective sequences 31 paraffin-embedded samples (23 GBM and 8 AA). The samples were obtained from a group of Iranian patients affected with high-grade glioblastoma (HGG). The overall prevalence of PIK3CA mutations was 23% (7/31) for both tumor types (22% in GBM, and 25% in AA). Five mutations were detected in exon 20, p.Arg992Gln (c.2976G→A), p.Met1005Val (c.3014A→G), p.Ile1019→Val (c.3056A→G), p.Ser1008Cys (c.3024C→G), and p.Asn1044Asp (c.3130A→G), and one mutation in exon 9, p.Glu545Ala (c.1634A→C). Additionally exons 4–8 of P53 gene in four unrelated young patients, who showed no mutations in PIK3CA exons 9 and 20, were analyzed. Three mutations were identified: p.Pro72Ala (c.214C→G), g.11608G→T (homozygote splice mutation), and p.Thr170Thr (c.510G→A silent mutation). In conclusion, mutation detection in PIK3CA in patients with a high degree of malignancy and early age at diagnosis should be included in molecular diagnostic protocols, also with regard to possible upcoming therapies.     

Mutation of nucleotide 1,762 in the core promoter region during hepatitis B e seroconversion and its relation to liver damage in hepatitis B e antigen carriers

In chronic hepatitis B virus (HBV) infection, mutations develop frequently at nucleotides 1,762/1,764 in the X protein open reading frame, where the core promoter is also located. By using a modified allele-specific polymerase chain reaction method, the longitudinal emergence of the A→T mutation at nucleotide 1,762 was studied in relation to precore mutations, genotype, and liver damage. First, samples from 38 carriers that were drawn before and after hepatitis B e (HBe) seroconversion were tested. T-1,762 mutant strains increased during HBe seroconversion (P = 0.004). In the HBe antigen-negative (HBeAg⁻) phase, T-1,762 mutants were found in 71% (12 of 17) of patients without compared with 33% (6 of 18) of patients with a concomitant precore mutation that prevents HBeAg synthesis (P = 0.08). Second, in 55 HBeAg⁺ patients, the T-1,762 mutant was found to be associated with more liver inflammation (P = 0.04) and fibrosis (P = 0.02), as measured by histology activity index (HAI) scores. The results show that the nucleotide (nt) 1,762 A→T mutation often develops during HBe seroconversion, particularly in strains without precore mutations that prevent HBeAg production. For unknown reasons, the T-1,762 mutant was rare in genotype B strains. The presence of a T-1,762 mutant in the HBeAg⁺ phase may be useful for identifying immunoactivation in previously immunotolerant carriers, which could be valuable for selecting patients for interferon therapy. J. Med. Virol. 55:185–190, 1998. © 1998 Wiley-Liss, Inc.     

Ataxia-telangiectasia in the Japanese population: Identification of R1917X,W2491R,R2909G,IVS33+2T→A,and 7883del5, the latter two being relatively common mutations

We analyzed the data regarding six Japanese ataxia-telangiectasia (A-T) patients from four unrelated families, at the DNA level, to search for possible common mutations in the Japanese population. Among eight mutant alleles in the four families, c. 4612del165 (exon 33 skipping) was identified in two alleles, and c. 5749A to T (R1917X), c. 7471T to C (W2491R), c.7883del5, and c. 8725A to G (R2909G) were identified in one allele each. We found no mutations in the other two alleles. The IVS33+2T→A mutation was identified at the genomic level as the cause of exon 33 skipping. We also identified the IVS33+2T→A mutation in a Japanese patient ATL105 who was previously found to be a homozygote of c. 4612del165. W2491R and R2909G mutations were not detected in more than 100 control Japanese alleles. The latter is located in a highly conserved PI-3 kinase domain and is a completely conserved residue among ATM-related proteins. Taken together with previously documented mutations in five other Japanese A-T patients, IVS33+2T→A and 7883del5 were identified in four and five alleles, respectively, in a total of 18 mutant alleles of Japanese A-T patients. These results suggest that these two mutations are relatively common mutations in the Japanese population. Hum Mutat 12:338–343, 1998.© 1998 Wiley-Liss, Inc.     

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

Farber lipogranulomatosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene. In the largest ever study, we identified and characterized ASAH1 mutations from 11 independent Farber disease (FD) families. A total of 13 different mutations were identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven mutations were exclusive to the Indian population. The IVS6+4A>G splice and IVS5‐16delTTTTC PPT deletion mutations resulted in skipping of exon 6 precluding thereby the region responsible for cleavage of enzyme precursor. A missense mutation (p.V198A) resulted in skipping of exon 8 due to inactivation of an exonic splicing enhancer (ESE) element. This is the first report of mutations affecting PPT and ESE in the ASAH1 gene resulting in FD.     

Genetic Heterogeneity of Beta Thalassemia in Lebanon Reflects Historic and Recent Population Migration

Beta thalassemia is an autosomal recessive disorder characterized by reduced (β⁺) or absent (β⁰) beta‐globin chain synthesis. In Lebanon it is the most predominant genetic defect. In this study we investigated the religious and geographic distribution of the β‐thalassemia mutations identified in Lebanon, and traced their precise origins. A total of 520 β‐globin chromosomes from patients of different religious and regional backgrounds was studied. Beta thalassemia mutations were identified using Amplification Refractory Mutation System (ARMS) PCR or direct gene sequencing. Six (IVS‐I‐110, IVS‐I‐1, IVS‐I‐6, IVS‐II‐1, cd 5 and the C>T substitution at cd 29) out of 20 β‐globin defects identified accounted for more than 86% of the total β‐thalassemia chromosomes. Sunni Muslims had the highest β‐thalassemia carrier rate and presented the greatest heterogeneity, with 16 different mutations. Shiite Muslims followed closely with 13 mutations, whereas Maronites represented 11.9% of all β‐thalassemic subjects and carried 7 different mutations. RFLP haplotype analysis showed that the observed genetic diversity originated from both new mutational events and gene flow from population migration. This study provides information about the types and distribution of β‐thalassemia mutations within each religious group and geographic region, which is essential for the implementation of screening and prevention programs.     

Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population

Glycogen storage disease type Ia (GSDIa) is a severe autosomal recessive disorder caused by deficiency of the enzyme D-glucose-6-phosphatase (G6Pase). While numerous mutations have been found in cosmopolitan European populations, Ashkenazi Jewish (AJ) patients appear to primarily carry the R83C mutation, but possibly also the Q347X mutation found generally in Caucasians. To determine the frequency for both these mutations in the AJ population, we tested 20,719 AJ subjects for the R83C mutation and 4,290 subjects for the Q347X mutation. We also evaluated the mutation status of 30 AJ GSDIa affected subjects. From the carrier screening, we found 290 subjects with R83C, for a carrier frequency for this mutation of 1.4%. This carrier frequency translates into a predicted disease prevalence of 1 in 20,000, five times higher than for the general Caucasian population, confirming a founder effect and elevated frequency of GSDIa in the AJ population. We observed no carriers of the Q347X mutation. Among the 30 GSDIa affected AJ subjects, all were homozygous for R83C. These results indicate that R83C is the only prevalent mutation for GSDIa in the Ashkenazi population.     

Premarital and prenatal screening for cystic fibrosis: experience in the Ashkenazi Jewish population.

PURPOSE: Since the early 1990s, Dor Yeshorim (DY) and the Mount Sinai School of Medicine (MSSM) have conducted premarital and prenatal carrier screening for cystic fibrosis (CF) in the Ashkenazi Jewish (AJ) population as part of their genetic testing programs, respectively. Together, over 170,000 screenees have been tested. In this study, we report the CF mutation frequencies in over 110,000 screenees who reportedly were of 100% AJ descent from the DY program and MSSM. In addition, the CF mutation frequencies in a group of > 7,000 screenees for AJ diseases who were of < 100% AJ descent are reported. METHODS: Testing for CF mutations was performed by either PCR and restriction digestion or ASO hybridization analyses at MSSM or sent to various academic and commercial laboratories by DY. RESULTS: The overall (and individual) carrier frequency for the five common AJ mutations, W1282X (0.020), DeltaF508 (0.012), G542X (0.0024), 3849+10kb C>T (0.0020), and N1303K (0.0016), among screenees who were 100% AJ was 1 in 26; when D1152H and the rare 1717-1G>A were included, the overall carrier frequency increased to approximately 1 in 23. In four families with D1152H, five compound heterozygotes for D1152H and W1282X (n = 2), DeltaF508 (1) or 3849+10kb C>T (1) were identified. In contrast, the carrier frequency for screenees reporting < 100% AJ descent was approximately 1 in 30 for the seven mutations. CONCLUSIONS: The carrier frequency for five common CF mutations in a large 100% AJ sample increased from 1 in 26 to 1 in 23 when D1152H was included in the panel. Addition of D1152H to mutation panels when screening the AJ population should be considered because compound heterozygosity is associated with a variable disease phenotype. Further studies to delineate the phenotype of CF patients with this mutation are needed.