Carrier Frequency Of Mutation Research Articles

Частота носительства в российской популяции мутаций в генах GJB2 и GALT, ассоциированных с развитием нейросенсорной тугоухости и галактоземии

Статья продолжает цикл работ, посвященных определению частоты носительства в российской популяции мутаций, ассоциированных с развитием распространенных моногенных заболеваний. Целью исследования было установление частоты распространенных в российской популяции мутаций в генах GJB2 и GALT у доноров первичной кроводачи. При генотипировании 1000 доноров первичной кроводачи, идентифицирующих себя как русских и постоянно проживающих на территории Российской Федерации, обнаружены 37 носителей мутаций в гене GJB2, ассоциированных с развитием нейросенсорной тугоухости (частота в выборке составила 3,7 %, или 1 : 27), и 6 носителей мутаций в гене GALT, ассоциированных с развитием галактоземии (частота в выборке — 0,6 %, или 1 : 167). Выявлен 1 случай сочетанного носительства мутаций, и, таким образом, всего обнаружены 42 носителя мутаций в генах GJB2 и GALT (частота в выборке — 4,2 %, или 1 : 24).

Absence of 185delAG and 6174delT Mutations among Breast Cancer Patients of Eastern India.

The incidence of breast cancer in India is on the rise and is rapidly becoming the number one cancer in females, pushing the cervical cancer to the second position. Most of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in two tumor suppressor genes BRCA1 and BRCA2. Alterations in these genes have been reported in different populations, some of which are population- specific mutations showing founder effects. Two specific mutations in the BRCA1 (185delAG) and BRCA2 (6174delT) genes have been reported to be of high prevalence in different populations. The aim of this study was to estimate the carrier frequency of 185delAG and 6174delT mutations in eastern Indian breast cancer patients. We selected 231 histologically confirmed breast cancer patients from our tertiary cancer care center in eastern India. Family history was obtained by interview or a self-reported questionnaire. The presence of the mutation was investigated by allele specific duplex/multiplex-PCR on genomic DNA extracted from peripheral blood. A total of 231 patients (age range: 26-77 years), 130 with a family history and 101 without were screened. The two founder mutations 185delAG in BRCA1 and 6174delT in BRCA2 were not found in any of the subjects. This was confirmed by molecular analysis. Our findings suggest that these BRCA mutations may not have a strong recurrent effect on breast cancer among the eastern Indian population. The contribution of these founder mutations to breast cancer incidence is probably low and could be limited to specific subgroups. This may be particularly useful in establishing further pre-screening strategies.

Carrier frequency of the GJB2 mutations that cause hereditary hearing loss in the Japanese population.

Hearing impairment is one of the most common sensory disorders that affect ~1 in 1000 children, and half of them are considered to be hereditary. Information about the carrier frequencies of mutations that underlie autosomal recessive disorders is indispensable for accurate genetic counseling to predict the probability of patients' children's disease. However, there have been few reports specific to the Japanese population. GJB2 mutations are reported to be the most frequent cause of hereditary hearing loss, and the mutation spectrum and frequency of GJB2 mutations were reported to vary among different ethnic groups. In this study, we investigated the carrier frequency of GJB2 mutations and the mutation spectrum in 509 individuals randomly selected from the general Japanese population. We show that the carrier frequencies of the two most common pathogenic mutations are 1.57% (8/509) for c.235delC and 1.77% (9/509) for p.Val37Ile. In addition to these mutations, we found two pathogenic variants (p.[Gly45Glu;Tyr136*] and p.Arg143Trp), and the total carrier frequency was estimated to be around 3.73% (19/509). We also detected six unclassified variants, including two novel variants (p.Cys60Tyr and p.Phe106Leu), with the former predicted to be pathogenic. These findings will provide indispensable information for genetic counseling in the Japanese population.

A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population.

BackgroundThe frequency of BRCA1 and BRCA2 mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 mutations, a defined subgroup of 116 cases were investigated for all mutations previously reported in this population.MethodsA PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific mutations that have ever been reported in French Canadians, which included the six mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window.ResultsA targeted analysis of six mutations identified 34/439 (7.7%) mutation carriers and at least two mutation carriers for each mutation screened were found. The BRCA1:C4446T mutation was the most frequently identified variant (15/34, 44.1%) among mutation-positive cases. The expanded mutation screen that also included 13 additional variants identified 19/116 (16.4%) mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with mutations identified in 19.2% (n = 14) serous cases.ConclusionsOur results reaffirm that specific BRCA1 and BRCA2 mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-015-0124-8) contains supplementary material, which is available to authorized users.

Визначення загальної частоти носійства мутації 35delG гена конексину-26 серед новонароджених Дніпропетровської та Запорізької областей

Визначення загальної частоти носійства мутації 35delG гена конексину-26 серед новонароджених Дніпропетровської та Запорізької областей

MALDI-TOF-MS based diagnosis and analysis of newborn hereditary deafness screening in Wuxi, Jiangsu Province

Objective To investigate the hot spots of genetic mutations that are responsible for hearing loss of newborns and the carrier frequencies of varies mutations, and also, to set up a clinical pattern for newborn hearing concurrent genetic screening in Wuxi. Methods A total of 2 796 newborns participated in this study were all born in Wuxi Maternity and Child Health Care Hospital during 2013-2014. Twenty hot mutation spots of four genes (i.e. GJB2, GLB3, SLC26A4, 12s rRNA) were chosen according to the latest epidemiologic study and were analyzed with matrix-assisted laser desorption ionization-time-of-flight mass spectrometry ( MALDI-TOF-MS). OAE and AABR methods were both used to help with the diagnosis of newborn hearing loss. Results 158 of 2 796 newborns tested (5.65%) were positive with at least one hot mutation spot. The number of positively tested single site mutation were 152 (5.44%), while the number of positively tested compound heterozygous mutations were 6 (0.21%). The positive mutation sites in GJB2 and SLC26A4 ranked 88.61% among all the positive mutation sites tested. Mutation site 235delC within GJB2 gene were hottest positive site with a number of 73 newborns, followed by IVS7-2A>G within SLC26A4 (18.99%, 30/158). Three 1555A>G homozygous mutations were also found in 12s rRNA. Four deafness newborns were found with newborn hearing concurrent genetic screening. Conclusions In comparison to the conventional detection methods, there could be more detection sites, greater coverage , and high throughput in MALDI-TOF-MS, and it would provid valuable guidance for newborns in the future. Key words: Hearing loss; Connexins; Membrane transport proteins; Mutations; Spectrometry, mass, matrix-Assisted laser desorption-ionization; Neonatal screening

Differential effects of severe vs mild GBA mutations on Parkinson disease.

To better define the genotype-phenotype correlations between the type of GBA (glucosidase, beta, acid) mutation, severe or mild, and the risk and age at onset (AAO), and potential mechanism of Parkinson disease (PD). We analyzed 1,000 patients of Ashkenazi-Jewish descent with PD for 7 founder GBA mutations, and conducted a meta-analysis of risk and AAO according to GBA genotype (severe or mild mutation). The meta-analysis included 11,453 patients with PD and 14,565 controls from worldwide populations. The statistical analysis was done with and without continuity correction (constant or empirical), considering biases that could potentially affect the results. Among Ashkenazi-Jewish patients with PD, the odds ratios for PD were 2.2 and 10.3 for mild and severe GBA mutation carriers, respectively. The observed frequency of severe GBA mutation carriers among patients with PD was more than 4-fold than expected (4.4% vs 0.9%, respectively, p < 0.0001, Fisher exact test). In the different models of the meta-analysis, the odds ratios for PD ranged between 2.84 and 4.94 for mild GBA mutation carriers and 9.92 and 21.29 for severe GBA mutation carriers (p < 1 × 10(-6) for all analyses). Pooled analysis demonstrated AAO of 53.1 (±11.2) and 58.1 (±10.6) years for severe and mild GBA mutation carriers, respectively (p = 4.3 × 10(-5)). These data demonstrate that mild and severe heterozygous GBA mutations differentially affect the risk and the AAO of PD. Our results have important implications for genetic counseling and clinical follow-up.

Carrier Frequency of Congenital Leptin Deficiency in Central Punjab Region of Pakistan

Congenital leptin deficiency is a rare autosomal recessive disorder, characterized by hyperphagia and early onset obesity. Worldwide data on this disorder includes only 25 cases out of this only six pathogenic mutations have been reported in the leptin gene. Most of these cases have been reported in Central Punjab region of Pakistan, harboring a (p.Gly133fsX145) mutation in homozygous state. This mutation has founder effect in Arain caste from Central Punjab region of Pakistan. In this study, carrier frequency of (p.Gly133fsX145) mutation was determined in 50 individuals belonging to Arain caste. Analysis of amplicons contains p.Gly133fsX145 mutation were analyzed by different techniques such as SSCP, Heteroduplex analysis and sequencing. Mutation was not found in any individual studied. This finding suggests that frequency of (p.Gly133fsX145) mutation in Arain caste is not as higher as its predicted founder effect in congenitally obese children of this caste was anticipated.

Beta-Glucocerebrosidase Gene Mutations P.Asn409Ser and P.Leu483Pro in Polish Patients with Parkinson's Disease

Background: The aim of his study was to evaluate the frequency of two most frequent GBA gene mutations in heterozygote state in patients with early and later onset Parkinson's disease in Polish populations. Methods and findings: Patients with Parkinson's disease; 115 non-demented with early onset disease (<45 year-old) and 155 patients with onset over 45 year-old were recruited to the study. The p.Asn409Ser and p.Leu483Pro screening was performed with the PCR-RFLP and direct sequencing methods. In the group of 270 PD patients, 11 heterozygotes for mutations in the GBA gene were identified (carrier frequency 4.07%). Among patients with early onset disease carrier frequency was 4.34% compared to 3,87% in the group of later onset. Conclusion: The study yielded that carrier frequency of GBA mutation in polish population was comparable to other European populations p.Asn409Ser mutation dominates in patients with early onset PD disease

Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease

BackgroundEzetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann–Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug.MethodsWe sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease.ResultsWith sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%).ConclusionsNaturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.)

Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer

Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers.

Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association.

Recently, the interest has focused on the increased prevalence of thrombophilic defects in women with gestational complications. To explore whether women with early recurrent pregnancy loss (RPL) are at increased risk of being carriers of the Factor V Leiden (FVL) mutation compared to those who have a normal reproductive history. A manual and electronic literature search was undertaken to identify studies with a case-control population of women with two or more first trimester RPLs of undetermined origin and age- and ethnicity-matched control group with normal reproductive history and at least one full-term delivery. Both groups were screened for FVL mutation. A quality assessment was performed according to the pre-established validity criteria and using the Cochrane handbook guidelines for observational studies. The combinability of studies was assessed by clinical and statistical methods (Breslow-Day's test of homogeneity). Quantitative data were abstracted with regard to the prevalence of FVL mutation in the case and control group, and 2 × 2 tables were created. The ratio comparing the odds of FVL mutation in women with early RPL with the odds of FVL mutation in women with normal reproductive outcome was calculated with its 95% confidence interval (CI) by Mantel-Haenszel method. Nine studies met the inclusion criteria and were selected for review. A total of 2,147 women were screened for the FVL mutation, 1,305 women with early RPL, and 842 women with no gestational complications. Women with early RPL had indeed a statistically significantly increased carrier frequency of FVL mutation, the common OR being 1.68 (95% CI: 1.16-2.44). FVL carrier state may increase the susceptibility for early RPL. Testing for FVL mutation should be considered in women with unexplained early RPL and thrombophylaxis has been suggested in women with unexplained RPL associated with FVL mutation.

Hypothesis: Possible respiratory advantages for heterozygote carriers of cystic fibrosis linked mutations during dusty climate of last glaciation

This paper puts forward a new hypothesis to interpret the high carrier frequency of CFTR mutations in individuals of European descent. The proposed heterozygote advantage factor is related to the specific climate conditions in Europe during the last 50ky that might have heavily compromised the respiratory function of our ancestors in Eurasia. A large part of the last 50ky was cold, and the coldest period was the Last Glacial Maximum (LGM) (26.5 to 19kya). The global climate was dry with a dust-laden atmosphere (20 to 25 times more dust than the present level). High levels of atmospheric dust started more than 40kya and ended less than 10kya.Secretion of airway fluid is usually related to the submucosal tissue hydration, while salt reabsorption relies on activation of CFTRs that allow ENaCs to absorb salt and water. The water loss by evaporation depends on the air humidity and flow rate. Salt accumulation in the mucus is normally prevented by reabsorption of Na+ and Cl− by epithelial cells if the presence of functional CFTRs is normal.If one gene for CFTR is mutated, the number of functional CFTRs is reduced and this limits the capacity of salt reabsorption by epithelial cells. This means that evaporation makes the airway fluid more hypertonic, and osmotic forces bring more water from the interstitial space, thus leading to a new balance in mucosal fluid traffic. Increased osmolarity and volume of airway fluid can be more moveable in cases when evaporation and dust exposure is increased.If both CFTR genes are mutated, low number of functional CFTRs diminishes salt resorption of epithelial cells. Salt accumulated in the mucous fluid within respiratory ducts, as previously described. The hypertonic ductal content forces more water and some electrolytes to enter the airway fluid from the interstitial fluid, and evaporation leads to further concentration of thick immobile mucus.The proposed interpretation is that CFTR mutations have spread among our ancestors that roamed the central Eurasia after the LGM. The heterozygote individuals might have benefitted from the limited water resorption in their respiratory mucosa that allowed improved airway cleansing.

Subgroups of familial and aggressive prostate cancer with considerable frequencies of BRCA2 mutations.

One of the known risk factors for prostate cancer (PrCa) is germline mutations in the BRCA2 gene. Previous searches for clinical characteristics which could identify a subgroup of patients enriched for mutation carriers revealed early onset and aggressive PrCa as useful parameters, but they are rather unspecific. Identification of BRCA2 mutation carriers by sequencing all exons of BRCA2 in a German cohort of 382 familial PrCa cases and of 92 sporadic PrCa cases with early onset (≤60 years). To define a subgroup of PrCa patients enriched for BRCA2 mutation carriers, we used clinical parameters including a detailed family history (FH) for PrCa and breast cancer. Five BRCA2 mutations and ten variants of unknown significance (VUS) were identified. While the VUS were evenly distributed among the groups, mutation carriers were lacking from the sporadic cases and over represented among familial cases with aggressive disease. High prostate specific antigen (PSA) at diagnosis (>20 ng/ml) was the only criterion with significant enrichment of mutation carriers (6.4%, P = 0.0005). In men with aggressive disease, death from PrCa (6.3% including FH of lethal PrCa; P = 0.05) and FH of both prostate and breast cancer (4.8%; P = 0.3) increased the frequency of mutation carriers. Larger studies and/or meta-analyses are needed to validate these parameters. We have identified three potentially useful criteria, high PSA, death from PrCa (patient or FH), and aggressive PrCa in combination with FH of breast and prostate cancer. If confirmed, they may become useful for the decision which patients may benefit from BRCA2 testing.

Inherited metabolic diseases in the Southern Chinese population: spectrum of diseases and estimated incidence from recurrent mutations

Inherited metabolic diseases (IMDs) are a large group of rare genetic diseases. The spectrum and incidences of IMDs differ among populations, which has been well characterised in Caucasians but much less so in Chinese. In a setting of a University Hospital Metabolic Clinic in Hong Kong, over 100 patients with IMDs have been seen during a period of 13 years (from 1997 to 2010). The data were used to define the spectrum of diseases in the Southern Chinese population. Comparison with other populations revealed a unique spectrum of common IMDs. Furthermore, the incidence of the common IMDs was estimated by using population carrier frequencies of known recurrent mutations. Locally common diseases (their estimated incidence) include (1) glutaric aciduria type 1 (∼1/60,000), (2) multiple carboxylase deficiency (∼1/60,000), (3) primary carnitine deficiency (∼1/60,000), (4) carnitine-acylcarnitine translocase deficiency (∼1/60,000), (5) glutaric aciduria type 2 (∼1/22,500), (6) citrin deficiency (∼1/17,000), (7) tetrahydrobiopterin-deficient hyperphenylalaninaemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency (∼1/60,000), (8) glycogen storage disease type 1 (∼1/150,000). In addition, ornithine carbamoyltransferase deficiency and X-linked adrenoleukodystrophy are common X-linked diseases. Findings of the disease spectrum and treatment outcome are summarised here which may be useful for clinical practice. In addition, data will also be useful for policy makers in planning of newborn screening programs and resource allocation.

The Ashkenazi Jewish carrier screening panel: evolution, status quo, and disparities.

Although prenatal/preconception carrier screening recommendations for individuals of Ashkenazi Jewish descent (AJ) were published by American College of Medical Genetics and Genomics (2008) and American College of Obstetrics and Gynecology (2009), scientific advances have led to widely varied screening panels. Mutation carrier frequencies are sometimes based on small, homogeneous AJ populations. This study sought to update the state of AJ screening for the obstetrician by assessing laboratory screening panel compositions as well as assessing literature and laboratory carrier frequencies for common AJ mutations. A literature review (1991-2013) was performed for AJ disease carrier frequencies. AJ screening data from six screening laboratories were collected. AJ panel composition was compared across 16 commercial and academic laboratories. Overall literature and laboratory carrier frequencies of AJ mutations were similar, although the Walker-Warburg syndrome laboratory carrier frequency was almost twice that in the literature. Laboratory AJ disease panel composition varied widely, from 8 to 25 diseases. Current AJ panels vary widely by laboratory, resulting in disparate levels of screening. Consideration of an updated professional standard for prenatal/preconception AJ screening based on carrier frequency rates, level of disease burden, availability of screening, and cost of technology may be useful in providing equitable and appropriate care for those planning a pregnancy.

Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets.

Data from massively parallel sequencing or 'Next Generation Sequencing' of the human exome has reached a critical mass in both public and private databases, in that these collections now allow researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single nucleotide polymorphism (SNP) or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes, we analyzed the causative gene for the disorder Smith-Lemli-Opitz Syndrome (SLOS), the 7-dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening.

Clinical and genetic characteristics of mexican patients with juvenile presentation of niemann-pick type C disease.

Niemann-Pick type C disease (NPC) is a rare lysosomal disease with a protean presentation, ranging from a fatal neonatal course with visceromegaly to an adult presentation with only neurological or psychiatric symptomatology. In this report we describe the genetic and clinical characteristics of 3 Mexican patients from different families with juvenile presentation of NPC. Clinical examination, imaging of central nervous and gastrointestinal system, and EEG were performed. Genetic studies include sequencing and deletion/duplication analysis of NPC1 and NPC2 genes. All patients presented with cognitive impairment, ataxia, and supranuclear vertical gaze palsy; one case had gelastic cataplexy. Also they developed epilepsy and cortical atrophy and two patients had thinning of corpus callosum. The 3 patients were compound heterozygotes for NPC1 sequence variants, including 5 missense and 1 nonsense mutations: p.P1007A and p.F1087L in Case 1; p.Q921P and p.G992R in Case 2; and p.R348∗ and p.V1165M in case 3. Mexican patients with juvenile NPC presented with a variable clinical phenotype and compound heterozygosity. This suggests a relative high frequency of mutation carriers as it is reported for European population. Consequently, clinicians should consider NPC as a diagnosis possibility in any adolescent or young adult patient with juvenile dementia and/or ataxia, even in absence of gelastic cataplexy and supranuclear vertical gaze palsy.

Carrier screening for spinal muscular atrophy in 4719 pregnant women in Shanghai region

Spinal muscular atrophy (SMA) is a common and fatal autosomal recessive disorder. Approximately 94% of SMA patients are caused by homozygous deletion of SMN1 gene. SMA carrier screening is recommended considering the high carrier frequency (1 in 35-50) as well as severity of the disease. A prospective population-based cohort study was carried out on 4719 pregnant women from Shanghai region. Copy numbers of SMN1 and SMN2 genes were effectively determined with denaturing high performance liquid chromatography (DHPLC) technique. The method has detected 94% of SMA cases with deletion or conversion of the SMN1 genes. Ninety SMA carriers with only one copy of the SMN1 gene were identified among the 4719 pregnant woman. The carrier rate was 1.9%. Respectively, 1.2% and 0.6% of the carriers were caused by SMN1 gene deletion and SMN1 gene conversion. Through this study, we have determined the frequency of SMA mutation carriers in a population of pregnant women. The result may provide a basis for genetic counseling in order to reduce the rate of SMA affected births.

Alpha thalassemia gene mutations in neonates from Mazandaran, Iran, 2012

AimAlpha thalassemia is one of the most prevalent disorders worldwide and carrier frequency of the disease is varied in different parts of the world. Although different studies in Iran and Mazandaran province have been carried out to identify different mutations of alpha globin gene among people with low hematological indices, frequencies of these mutations were unknown in general population, and thus the aim of this study was to evaluate the carrier frequencies of alpha globin gene mutations among neonates in Mazandaran.Material and methodsFour hundred and twelve neonates were collected from a delivery ward of a hospital in Sari. DNA was extracted from their cord blood samples using phenol-chloroform-based method. For the detection of five common alpha thalassemia gene mutations, multiplex-GAP-PCR and PCR-RFLP methods were applied.ResultsSixty three (15.29%, confidence interval, CI 95%: 11.81–18.77) of investigated neonates had at least one of the five evaluated mutations. The -α3.7 deletion had the highest frequency (9.7%, CI 95%: 6.84–12.56) and none of the neonates had –Med double gene deletion. The -α4.2 deletion, αααanti3.7 triplication, and α−5nt mutations had frequencies of 4.1% (CI 95%: 2.19–36.01), 2.2% (CI 95%: 0.78–3.62), and 0.49% (CI 95%: −0.18–1.16), respectively.DiscussionOur study showed that in most of the alpha thalassemia carriers just one copy of alpha globin gene was absent and they are not at risk of having children with Hb H disease or hydrops fetalis; however, up to 2.2% of neonates were carriers for αααanti3.7 triplication and they will be at risk for having a child with thalassemia intermediate if they marry a person which is a carrier of beta thalassemia.