Mahdi Malekpour

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US

GJB2 MUTATIONS: PASSAGE THROUGH IRAN

2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.

Sensorineural deafness and male infertility: a contiguous gene deletion syndrome

Hereditary hearing loss (HHL) is a very common disorder. When inherited in an autosomal recessive manner, it typically presents as an isolated finding. Interestingly and unexpectedly, in spite of extreme heterogeneity, mutations in one gene, GJB2, are the most common cause of congenital severe‐to‐profound deafness in many different populations. In this study, we assessed the contributions made by GJB2 mutations and chromosome 13 g.1777179_2085947del (the deletion more commonly known as del (GJB6‐D13S1830) that includes a portion of GJB6 and is hereafter called Δ(GJB6‐D13S1830)) to the autosomal recessive non‐syndromic deafness (ARNSD) genetic load in Iran. Probands from 664 different nuclear families were investigated. GJB2‐related deafness was found in 111 families (16.7%). The carrier frequency of the 35delG mutation showed a geographic variation that is supported by studies in neighboring countries. Δ(GJB6‐D13S1830) was not found. Our prevalence data for GJB2‐related deafness reveal a geographic pattern that mirrors the south‐to‐north European gradient and supports a founder effect in southeastern Europe.

Identification of three novel TECTA mutations in Iranian families with autosomal recessive nonsyndromic hearing impairment at the DFNB21 locus.

Background: Syndromic hearing loss that results from contiguous gene deletions is uncommon. Deafness-infertility syndrome (DIS) is caused by large contiguous gene deletions at 15q15.3. Methods: Three families with a novel syndrome characterised by deafness and infertility are described. These three families do not share a common ancestor and do not share identical deletions. Linkage was established by completing a genome-wide scan and candidate genes in the linked region were screened by direct sequencing. Results: The deleted region is about 100 kb long and involves four genes (KIAA0377, CKMT1B, STRC and CATSPER2), each of which has a telomeric duplicate. This genomic architecture underlies the mechanism by which these deletions occur. CATSPER2 and STRC are expressed in the sperm and inner ear, respectively, consistent with the phenotype in persons homozygous for this deletion. A deletion of this region has been reported in one other family segregating male infertility and sensorineural deafness, although congenital dyserythropoietic anaemia type I (CDAI) was also present, presumably due to a second deletion in another genomic region. Conclusion: We have identified three families segregating an autosomal recessive contiguous gene deletion syndrome characterised by deafness and sperm dysmotility. This new syndrome is caused by the deletion of contiguous genes at 15q15.3.

Two novel GALNT3 mutations in familial tumoral calcinosis.

Forty‐five consanguineous Iranian families segregating autosomal recessive nonsyndromic hearing loss (ARNSHL) and negative for mutations at the DFNB1 locus were screened for allele segregation consistent with homozygosity by descent (HBD) at the DFNB21 locus. In three families demonstrating HBD at this locus, mutation screening of TECTA led to the identification of three novel homozygous mutations: one frameshift mutation (266delT), a transversion of a cytosine to an adenine (5211C > A) leading to a stop codon, and a 9.6 kb deletion removing exon 10. In total, six mutations in TECTA have now been described in families segregating ARNSHL. All of these mutations are inactivating and produce a similar phenotype that is characterized by moderate‐to‐severe hearing loss across frequencies with a mid frequency dip. The truncating nature of these mutations is consistent with loss‐of‐function, and therefore the existing TECTA knockout mouse mutant represents a good model in which to study DFNB21‐related deafness.

A novel DFNA5 mutation does not cause hearing loss in an Iranian family

Familial tumoral calcinosis (TC) is characterized by elevated serum phosphate concentrations, normal or elevated 1,25(OH)2 vitamin D, as well as periarticular and vascular calcifications. Recessive mutations in the mucin‐like glycosyltransferase GalNAc transferase‐3 (GALNT3) and the phosphaturic hormone fibroblast growth factor‐23 (FGF23) have been shown to result in TC. In the present study, mutational analyses were performed on two patients with TC to determine the molecular basis of their diseases. Analysis of the first patient revealed a novel, homozygous base insertion (1102_1103insT) in GALNT3 exon 5 that results in a frameshift and premature stop codon (E375X). The second patient had a novel homozygous transition (1460 g>a) in GALNT3 exon 7, which caused a nonsense mutation (W487X). Both mutations are predicted to markedly truncate the mature GALNT3 protein product. Although the patients carry GALNT3 mutations, these individuals presented with low‐normal serum concentrations of intact biologically active FGF23 and high levels of C‐terminal FGF23. In order to discern a possible relationship between GALNT3 and FGF23 in TC, a comprehensive assessment of the reported TC mutations was also performed. In summary, we have detected novel GALNT3 mutations that result in familial TC, and show that disturbed serum FGF23 concentrations are present in our TC cases as well as in previously reported cases. These studies expand our current genetic understanding of familial TC, and support a pathophysiological association between GALNT3 and FGF23.

An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4

AbstractMutations in DFNA5 lead to autosomal dominant non-syndromic sensorineural hearing loss that starts at the high frequencies. To date, only three DFNA5 mutations have been described, and although different at the genomic DNA level, all lead to exon 8 skipping at the mRNA level. This remarkable fact has led towards the hypothesis that DFNA5-associated hearing loss is caused by a gain-of-function mutation and not by haplo-insufficiency as previously thought. Here, we describe a fourth DFNA5 mutation: the insertion of a cytosine at nucleotide position 640 (AF073308.1:_c.640insC, AAC69324.1:_p. Thr215HisfsX8). Unlike the previously described mutations, this frameshift mutation truncates the protein in exon 5 of the gene. Although the mutation was found in an extended Iranian family with hereditary hearing loss, it does not segregate with the hearing loss phenotype and is even present in persons with normal hearing. This fact provides further support for the hypothesis that DFNA5-associated hearing loss is caused by a gain-of-function mutation.

Two cochlear implants: halving the number of recipients

We report on three siblings with a novel mental retardation (MR) syndrome who were born to distantly related Iranian parents. The clinical problems comprised severe MR, cataracts with onset in late adolescence, kyphosis, contractures of large joints, bulbous nose with broad nasal bridge, and thick lips. Two patients also had uni- or bilateral iris coloboma. Linkage analysis revealed a single 10.4 Mb interval of homozygosity with significant LOD score in the pericentromeric region of chromosome 4 flanked by SNPs rs728293 (4p12) and rs1105434 (4q12). This interval contains more than 40 genes, none of which has been implicated in MR so far. The identification of the causative gene defect for this syndrome will provide new insights into the development of the brain and the eye.

Retaining health manpower in developing countries

1686 www.thelancet.com Vol 370 November 17, 2007 data from slightly fewer women being analysed in the PARIS review than in the Cochrane review. The strength of our analysis was that the use of IPD enabled us to classify individual women more accurately as having received antiplatelets for primary prevention, and by whether they were high or low risk at trial entry, rather than having to include all women from one particular trial in an analysis as was necessary in the Cochrane aggregate data review. Two factors might have contributed to the modest diff erences in data for fetal and neonatal deaths between the two reviews, as shown by M Chandiramani and colleagues. First, use of IPD allowed signifi cant recheck ing of the original data, which for some trials changed the overall result for this outcome. Second, the PARIS analyses used fetal or baby death before discharge as the defi nition of this outcome, rather than fetal or baby death at any time, as reported in the trials included in the Cochrane review. So, although the PARIS analysis included slightly fewer women, they had slightly more fetal or neonatal deaths. The net eff ect is a slight shift in both the relative risk and confi dence interval. Nevertheless, the relative risks from both reviews are similar, both suggesting a modest reduction (10%) in the relative risk of baby death. Although the PARIS analysis gives a slightly more conservative estimate of benefi t, which does not quite achieve signifi cance, we believe it represents a worthwhile eff ect, especially when coupled with a clear reduction in the risk of preterm birth which is also an impor tant outcome for mothers (and health-care systems). Although it will be interesting to explore the diff erences between results of the PARIS and Cochrane reviews further, we believe they give the same overall message and we reiterate that we believe the PARIS review is the most reliable analysis of the eff ect of antiplatelets in preventing preeclampsia and the most robust data to discuss with women when making decisions about care.

Clinical Application of Screening for GJB2 Mutations before Cochlear Implantation in a Heterogeneous Population with High Rate of Autosomal Recessive Nonsyndromic Hearing Loss

I was pleased to see the undergraduates’ concern about healthcare delivery in developing countries (May 16, p 1665). As they discuss, compensation could be a solution to the problem of migration, but it would only be a temporary one. The main reasons health-care workers migrate are to look for better opportunities, a better lifestyle, better education for their children, and safe working conditions. So unless home countries are able to give some hope in these regards, the migration of health-care workers from developing to developed countries will continue. The following options might help further. Bonding systems could require medical or nursing graduates to serve for a minimum number of years in the home country before going for further training. Such a scheme has helped rural Nepal keep hold of more of its young doctors in recent times. Increasing facilities such as schools, police posts, and the availability of telephone networks and the internet could help doctors to remain in the rural setting of developing countries where they are urgently needed. Finally, increasing both the numbers and skill sets of mid-level health-care workers such as health assistants and community medical assistants could boost the backbone of the health-care service in rural settings. Additionally, because the qualifi cation is not internationally recognised, such workers are less likely to migrate. So, rather than producing more doctors, shifting the focus to mid-level health care workers might help developing countries, at least in the delivery of basic health care and to move towards achieving the Millennium Development Goals.