Fatemeh Alasti

University of Antwerp, Antwerpen, VLG, Belgium

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Publications (19)58.36 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial arch anomalies, hearing loss and renal dysmorphology. Although haploinsufficiency of EYA1 and SIX1 are known to cause BOR, copy number variation analysis has only been performed on a limited number of BOR patients. In this study, we used high-resolution array-based comparative genomic hybridization on 32 BOR probands negative for coding-sequence and splice-site mutations in known BOR-causing genes to identify potential disease-causing genomic rearrangements. Of the >1,000 rare and novel copy number variants we identified, four were heterozygous deletions of EYA1 and several downstream genes that had nearly identical breakpoints associated with retroviral sequence blocks, suggesting that non-allelic homologous recombination seeded by this recombination hotspot is important in the pathogenesis of BOR. A different heterozygous deletion removing the last exon of EYA1 was identified in an additional proband. Thus, in total five probands (14 %) had deletions of all or part of EYA1. Using a novel disease-gene prioritization strategy that includes network analysis of genes associated with other deletions suggests that SHARPIN (Sipl1), FGF3 and the HOXA gene cluster may contribute to the pathogenesis of BOR.
    Human Genetics 07/2013; · 4.63 Impact Factor
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    Dataset: hoxa2
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    American Journal of Medical Genetics Part A 08/2011; 155A(8):2021-3. · 2.30 Impact Factor
  • Clinical Genetics 06/2011; 79(6):594-8. · 4.25 Impact Factor
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    ABSTRACT: Hearing loss (HL) is the most frequent sensory birth defect in humans. Autosomal recessive non-syndromic HL (ARNSHL) is the most common type of hereditary HL. It is extremely heterogeneous and over 70 loci (known as DFNB) have been identified. This study was launched to determine the relative contribution of more frequent loci in a cohort of ARNSHL families. Thirty-seven Iranian families including 36 ARNSHL families and 1 family with Pendred syndrome each with ≥ 4 affected individuals, from seven provinces of Iran, were ascertained. DFNB1 contribution was initially studied by DNA sequencing of GJB2 and linkage analysis using the relative STR markers. The excluded families were then subjected to homozygosity mapping for fifteen ARNSHL loci. Sixteen families were found to be linked to seven different known loci, including DFNB1 (6 families), DFNB4 (3 families +1 family with Pendred syndrome), DFNB63 (2 families), DFNB2 (1 family), DFNB7/11 (1 family), DFNB9 (1 family) and DFNB21 (1 family). DNA sequencing of the corresponding genes is in progress to identify the pathogenic mutations. The genetic causes were clarified in 43.2% of the studied families, giving an overview of the causes of ARNSHL in Iran. DFNB4 is ranked second after DFNB1 in the studied cohort. More genetic and epigenetic investigations will have to be done to reveal the causes in the remaining families.
    Iranian Journal of Public Health 01/2011; 40(2):34-48. · 0.41 Impact Factor
  • Human Genetics 04/2010; 127(4):471. · 4.63 Impact Factor
  • Human Genetics 04/2010; 127(4):468-9. · 4.63 Impact Factor
  • Human Genetics 01/2010; 127(1):116. · 4.63 Impact Factor
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    ABSTRACT: This study aimed to investigate the contribution of four common DFNB ("DFN" for deafness and "B" for auto-somal resessive locus) loci and GJB2 gene mutations (exon 2) in hearing impairment in individuals living in Markazi and Qom provinces of Iran. Forty consan-guineous Iranian families with at least three affected individuals in family or pedigree who suffer from an autosomal recessive non-syndromic congenital hear-ing impairment were the subjects of this study. Blood samples were taken from both hearing and non-hear-ing individuals, DNA was extracted and amplified by using specific primers for the coding region of GJB2 gene (exon 2). The PCR product of GJB2 gene was then sequenced. Also short tandem repeat (STR) markers amplified by using specific primers for loci DFNB2, DFNB3, DFNB4 and DFNB21. At least 2 microsatellite markers (STR) for each DFNB locus exceeding to 4-6 markers for the linked families were used. The amplified markers were analyzed by con-ventional Polyacrylamide Gel Electrophoresis followed by silver staining. Six families were homozygous or compound heterozygous for GJB2 mutations and were excluded from further studies. Linkage analysis was carried out for the remaining 34 families by genotyping the flanked STR markers of DFNB2, DFNB3, DFNB4 and DFNB21 loci. Six families showed linkage; includ-ing one family to DFNB2, two families to DFNB3 and three families to DFNB4 locus while no family showed linkage to DFNB21 locus. Undoubtedly, the best understanding of the genetic basis of hearing loss in Iranian population will be achieved by performing sim-ilar experiments in other provinces and also by analyz-ing more loci. Congenital deafness is the most prevalent sen-sorineural disorder that affects one in 1000 neonates with 50% genetic basis (Kalay et al., 2005; Ramshankar et al., 2003). Hereditary deafness is a genetically heterogeneous disorder that is classified as non-syndromic (70%) and syndromic. Non-syn-dromic hearing impairment can be further subdivided by the mode of inheritance. The majority of the non-syndromic cases (77%) show autosomal recessive inheritance while 22% are autosomal dominant and only 1% is X-linked or due to mitochondrial muta-tions (Petersena and Willemsb 2006; Mukherjee et al., 2003). More than 100 genes are estimated to be involved in hearing impairment and to date about 130 loci have been described in previous studies and 47
    Iranian Journal of Biotechnology 10/2009;
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    F Alasti, G Van Camp
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    ABSTRACT: Microtia is a congenital anomaly, characterised by a small, abnormally shaped auricle (pinna). It is usually accompanied by a narrow, blocked or absent ear canal. Microtia can occur as the only clinical abnormality or as part of a syndrome. The estimated prevalence of microtia is 0.8-4.2 per 10 000 births, and it is more common in men. Microtia can have a genetic or environmental predisposition. Mendelian hereditary forms of microtia with an autosomal dominant or recessive mode of inheritance, and some forms due to chromosomal aberrations have been reported. Several responsible genes have been identified, most of them being homeobox genes. Mouse models have been very useful to study these genes, providing valuable information on the development of the auditory system. In this article, we review the epidemiological characteristics of microtia and the environmental causes involved. In addition, we discuss the development of the auditory system, specifically the relevant aspects of external and middle ear development. The focus of this review is to discuss the genetic aspects of microtia and associated syndromes. The clinical aspects of various disorders involving microtia are also discussed in relation to the genes that are causing them.
    Journal of Medical Genetics 04/2009; 46(6):361-9. · 5.70 Impact Factor
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    ABSTRACT: Hearing loss is the most frequent sensorineural disorder affecting 1 in 1000 newborns. In more than half of these babies, the hearing loss is inherited. Hereditary hearing loss is a very heterogeneous trait with about 100 gene localizations and 44 gene identifications for non-syndromic hearing loss. Transmembrane channel-like gene 1 (TMC1) has been identified as the disease-causing gene for autosomal dominant and autosomal recessive non-syndromic hearing loss at the DFNA36 and DFNB7/11 loci, respectively. To date, 2 dominant and 18 recessive TMC1 mutations have been reported as the cause of hearing loss in 34 families. In this report, we describe linkage to DFNA36 and DFNB7/11 in 1 family with dominant and 10 families with recessive non-syndromic sensorineural hearing loss. In addition, mutation analysis of TMC1 was performed in 51 familial Turkish patients with autosomal recessive hearing loss. TMC1 mutations were identified in seven of the families segregating recessive hearing loss. The pathogenic variants we found included two known mutations, c.100C>T and c.1165C>T, and four new mutations, c.2350C>T, c.776+1G>A, c.767delT and c.1166G>A. The absence of TMC1 mutations in the remaining six linked families implies the presence of mutations outside the coding region of this gene or alternatively at least one additional deafness-causing gene in this region. The analysis of copy number variations in TMC1 as well as DNA sequencing of 15 additional candidate genes did not reveal any proven pathogenic changes, leaving both hypotheses open.
    Clinical Genetics 06/2008; 74(3):223-32. · 4.25 Impact Factor
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    ABSTRACT: Microtia, a congenital deformity manifesting as an abnormally shaped or absent external ear, occurs in one out of 8,000-10,000 births. We ascertained a consanguineous Iranian family segregating with autosomal-recessive bilateral microtia, mixed symmetrical severe to profound hearing impairment, and partial cleft palate. Genome-wide linkage analysis localized the responsible gene to chromosome 7p14.3-p15.3 with a maximum multi-point LOD score of 4.17. In this region, homeobox genes from the HOXA cluster were the most interesting candidates. Subsequent DNA sequence analysis of the HOXA1 and HOXA2 homeobox genes from the candidate region identified an interesting HOXA2 homeodomain variant: a change in a highly conserved amino acid (p.Q186K). The variant was not found in 231 Iranian and 109 Belgian control samples. The critical contribution of HoxA2 for auditory-system development has already been shown in mouse models. We built a homology model to predict the effect of this mutation on the structure and DNA-binding activity of the homeodomain by using the program Modeler 8v2. In the model of the mutant homeodomain, the position of the mutant lysine side chain is consistently farther away from a nearby phosphate group; this altered position results in the loss of a hydrogen bond and affects the DNA-binding activity.
    The American Journal of Human Genetics 05/2008; 82(4):982-91. · 11.20 Impact Factor
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    ABSTRACT: Mutations in the TECTA gene result in sensorineural non-syndromic hearing impairment. TECTA-related deafness can be inherited autosomal dominantly (designated as DFNA8/12) or autosomal recessively (as DFNB21). The alpha-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Six mutations in the TECTA gene have already been reported in families segregating autosomal recessive non-syndromic hearing impairment. In this study, seventy-five Iranian families segregating autosomal recessive non-syndromic hearing impairment were analyzed for homozygosity at the DFNB21 locus by genotyping two short tandem repeat markers closely linked to the TECTA gene. Allelic segregation consistent with possible linkage to the DFNB21 locus was found in 1/75 families studied. By sequencing all 23 coding exons of TECTA, a 16bp deletion (c.6203-6218del16) in exon 21, leading to a frameshift, segregating with the hearing loss was found. All 3 affected individuals of this family have moderate-to-severe hearing loss across all frequencies, which is more pronounced in the mid frequencies. This new mutation, as well as the six previously reported mutations in the TECTA gene, is inactivating. All of these mutations lead to an easily recognized audiometric profile of moderate to severe hearing impairment as presented by the family in this study too. The TECTA autosomal recessive non-syndromic deafness phenotype differs from the typical profound deafness phenotype that is seen in most families segregating autosomal recessive non-syndromic deafness. On the basis of the recognizable phenotype, we recommend mutation screening of TECTA in families with this hearing phenotype.
    International Journal of Pediatric Otorhinolaryngology 03/2008; 72(2):249-55. · 1.35 Impact Factor
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    ABSTRACT: 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 (5,211C > 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.
    American Journal of Medical Genetics Part A 07/2007; 143A(14):1623-9. · 2.30 Impact Factor
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    ABSTRACT: Mutations 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.
    Journal of Human Genetics 01/2007; 52(6):549-52. · 2.37 Impact Factor
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    Journal of Medical Genetics 06/2003; 40(5):360-3. · 5.70 Impact Factor
  • Fatemeh Alasti, Guy Van Camp, Richard JH Smith
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    ABSTRACT: Pendred syndrome (PDS) and DFNB4 comprise a phenotypic spectrum of hearing loss with or without other findings. Pendred syndrome is characterized by severe-to-profound bilateral sensorineural hearing impairment (that is usually congenital [or prelingual] and non-progressive), vestibular dysfunction, temporal bone abnormalities, and development of euthyroid goiter in late childhood to early adulthood. Variability of findings is considerable, even within the same family. DFNB4 is characterized by nonsyndromic sensorineural hearing impairment, vestibular dysfunction, and enlarged vestibular aqueduct (EVA). Thyroid defects are not seen in DFNB4. PDS and DFNB4 are diagnosed clinically in individuals with (1) hearing impairment that is usually congenital and often severe to profound, although mild-to-moderate progressive hearing impairment also occurs; and (2) bilateral dilation of the vestibular aqueduct (DVA, also called enlarged vestibular aqueduct or EVA) with or without cochlear hypoplasia; the presence of both DVA and cochlear hypoplasia is known as Mondini malformation or dysplasia. In addition, individuals with PDS have either an abnormal perchlorate discharge test or goiter (when no other etiology of the goiter is evident and perchlorate washout cannot be performed). Mutations in three known genes account for approximately half of PDS/DFNB4 cases: SLC26A4 (~50% of affected individuals), FOXI1 (<1% of affected individuals), and KCNJ10 (<1% of affected individuals), suggesting further genetic heterogeneity. Sequence analysis of SLC26A4 identifies disease-causing mutations in approximately 50% of affected individuals from either simplex or multiplex families. These persons are often compound heterozygotes for disease-causing variants in SLC26A4 although not infrequently only a single variant is detected. Molecular genetic testing of SLC26A4 is clinically available. Molecular genetic testing of FOXI1 and KCNJ10 is available on a research basis only Treatment of manifestations: Hearing habituation, hearing aids, and educational programs designed for the hearing impaired; consideration of cochlear implantation in individuals with severe-to-profound deafness; standard treatment of abnormal thyroid function. Surveillance: Semiannual or annual assessment of hearing and endocrine function. Baseline ultrasound of the thyroid with periodic ultrasound surveillance to monitor volumetric changes. Repeat audiometry initially every three to six months if hearing loss is progressive. Agents/circumstances to avoid: Weightlifting and contact sports. Pendred syndrome/DFNB4 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible when the family-specific mutations are known.
    GeneReviews™, Edited by Roberta A Pagon, Thomas D Bird, Cynthia R Dolan, Karen Stephens, Margaret P Adam; University of Washington, Seattle.
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    ABSTRACT: The standard method for immunoscreening of a cDNA expression library is time-consuming because of the production of a large proportion of false posi-tives during the first and second round of screening. This problem is more important when a sensitive chemiluminescence detection system is used. Due to the high sensitivity of the detection system, there is a need to avoid false positives which occur when the antibody reacts non-specifically. False positives are generally eliminated through absorption of the anti-body with the host bacteria and by eliminating any clones, which react with antibodies present in normal sera. Here we present a method of obtaining almost identical bacteriophage plates by culturing phage in parallel, and show that this technique produces posi-tive plaques in duplicate and eliminates false posi-tives. Using this method, we successfully screened a human fetal spinal cord lambda gt11 cDNA library using purified immunoglobulin G (IgG) from patients with multiple sclerosis (MS) and Guillain – Barre syn-drome (GBS).
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    Iranian J Pub Health. 40(2):34-48.