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Rafati M.,Avicenna Research Institute | Rafati M.,Comprehensive Genetic Center | Mohamadhashem F.,Avicenna Research Institute | Mohamadhashem F.,Tehran University of Medical Sciences | And 5 more authors.
European Journal of Medical Genetics | Year: 2016

"Disorganized Development of Skeletal Component" (DDSC) is a group of genetic skeletal dysplasia, caused by mutations in 9 genes including ACVR1. The most known ACVR1-related disorder is fibrodysplasia ossificans progressiva (FOP). FOP variants are frequently encountered with diagnostic challenges due to overlapping clinical manifestations and variable severity. Application of high throughput sequencing methods can overcome these limitations by simultaneous investigation of the entire ACVR1 gene together with other genes involved in disorders with similar manifestations. A 33-year-old man with an unusual skeletal dysplasia and no previous clinical diagnosis is presented in this study. Whole exome sequencing detected a novel c.737T>A (p.Phe246Tyr) mutation in ACVR1 gene. Detailed targeted variant analysis in 226 known genes associated with genetic skeletal disorders together with more specific targeted analysis in 9 genes associated with DDSC ruled out the involvement of other investigated genes. Proband's phenotypically normal father and brother had the same mutation in whom subsequent investigations showed subclinical radiographic findings.The clinical manifestations, the disease course, and the molecular findings of involvement of ACVR1 gene in this family are suggestive of "FOP variant" or an unusual ACVR1-related skeletal dysplasia. Moreover, this report has demonstrated the critical role of the next generation sequencing technique in characterizing such a rare disorder with variable and even no clinical manifestations, providing the opportunity for effective preventive measures such as preimplantation genetic diagnosis. © 2016 Elsevier Masson SAS. Source


Rafati M.,Tehran University of Medical Sciences | Rafati M.,Comprehensive Genetic Center | Seyyedaboutorabi E.,Islamic Azad University | Brujerdi R.,Islamic Azad University | And 3 more authors.
Clinical Dysmorphology | Year: 2012

Williams-Beuren syndrome (WBS), a contiguous gene deletion syndrome, mostly occurs sporadically. Although a few cases of familial WBS have been reported in the literature, molecular confirmation of the deletion has not been carried out in all of them. Here, we report on the eighth clinically and molecularly confirmed inherited WBS detected in a family with 'familial mental retardation.' A comprehensive screening approach to mental retardation that included stepwise karyotyping, assessment for fragile-X syndrome, subtelomeric rearrangements and known microdeletion/microduplication syndromes, and a genome-wide array-CGH study was applied. The father, the mother, and their daughter were all mentally handicapped with nonspecific clinical manifestations and dysmorphic features. The first child of the family died from multiple congenital anomalies. The father and his daughter, who had never been suspected to have WBS, were diagnosed as having a deletion of the WBS critical region. No other abnormalities were detected in the family. Unlike other previously reported cases, in which the disease was ascertained on the basis of clinical manifestations, the present report represents an example of the detection of cryptic chromosomal abnormalities in mental retardation patients by the stepwise application of high-throughput screening methods. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Rafati M.,Tehran University of Medical Sciences | Rafati M.,Comprehensive Genetic Center | Seyyedaboutorabi E.,Islamic Azad University at Tehran | Ghadirzadeh M.R.,Tehran Welfare Organization | And 11 more authors.
Molecular Cytogenetics | Year: 2012

Background: Interstitial Microdeletion and Microduplication syndromes have been proposed as a significant cause of sporadic intellectual disability (ID) but the role of such aberrations in familial ID has not yet been investigated. As the balanced chromosomal abnormalities commonly lead to the recurrent ID or multiple congenital anomalies, this study was designed to evaluate whether it was justified to investigate such aberrations in familial ID patients. Three hundred and twenty eight patients from 101 unrelated Iranian families with more than two ID patients in the first-degree relatives, have been investigated. Assessment of a panel of 21 common Microdeletion and Microduplication syndromes (CMMS) was carried out using Multiplex Ligation-Dependent Probe Amplification (MLPA) technique. Results: Among the families studied, 27.7% had 4-12, 35.6% had 3 and 36.6% had 2 affected individuals in the first-degree relatives. An autosomal dominant inheritance of Williams-Beuren syndrome (WBS) was detected in a family with no clinical suspicion of WBS. The prevalence of CMMS was therefore,0.99%. Conclusion: This is the first investigation of a panel of CMMS in a large sample set of "familial ID patients". The findings of this study showed the low prevalence of CMMSs in "familial ID" patients in spite of the significant contribution of such aberrations in "sporadic ID" which has a very useful practical impact by avoiding unnecessary diagnostic tests in "familial ID" patients. © 2012 Rafati et al; licensee BioMed Central Ltd. Source


Korzebor A.,Tehran University of Medical Sciences | Derakhshandeh-Peykar P.,Tehran University of Medical Sciences | Meshkani M.,Tehran University of Medical Sciences | Hoseini A.,Comprehensive Genetic Center | And 4 more authors.
Molecular Biology Reports | Year: 2013

Preimplantation genetic diagnosis (PGD) has been considered as an alternative to prenatal diagnosis for prevention of genetic disorders while avoiding the subsequent termination of pregnancy. However, the limited amount of template DNA available in a single diploid cell used for PGD leads to number of problems including an increased incidence of detectable contamination; amplification failure and allele drop out. Due to their highly polymorphic and amplifiable characteristics, short tandem repeat (STR) analysis has been proposed as a mean to overcome these limitations. Heterozygosity of the applied STRs is of paramount importance in their informativity, and should therefore be studied in any certain population. Here, for the first time, we report on the heterozygosity analysis of five STR markers (D5S1408, D5S1417, D5S610, D5S629 and D5S637) flanking to SMA gene region, to examine their applicability in the PGD for SMA disease. We have also investigated other statistical features of these markers and found that all of the five studied STRs were informative and four meet the Hardy-Weinberg equilibrium for the studied population. Furthermore, our results propose that similar approaches can be used for the PGD of other single gene disorders. © 2012 Springer Science+Business Media Dordrecht. Source


Rafati M.,Tehran University of Medical Sciences | Rafati M.,Comprehensive Genetic Center | Ghadirzadeh M.R.,Tehran Welfare Organization | Heshmati Y.,Tehran Welfare Organization | And 8 more authors.
Molecular Cytogenetics | Year: 2012

Background: Cryptic subtelomeric rearrangements have been proposed as a significant cause of sporadic intellectual disability (ID) but the role of such aberrations in familial ID has not yet been studied. As positive family history of ID had been proposed as an important and significant predicting factor of subtelomeric rearrangements, it was assumed that the contribution of subtelomeric aberrations in familial ID would be much more than the sporadic ones. Three hundred and twenty two patients from 102 unrelated families with more than two ID patients in the first degree relatives have been investigated. Assessment of subtelomeric rearrangements were carried out using Multiplex Ligation-Dependent Probe Amplification (MLPA) technique. Detected aberrations were then confirmed by Fluorescence in Situ Hybridization (FISH) method. Results: Among the families studied, 27.4% had 4-12, 36.3% had 3 and 36.3% had 2 affected individuals in the first degree relatives. One unbalanced translocation and 4 polymorphic changes were detected. The prevalence of clinically significant subtelomeric rearrangements was 0.98%. Conclusion: This is the first investigation of subtelomeric aberrations in a large sample set of familial ID patients. Our results show that the contribution of subtelomeric rearrangements to familial ID is not as much as what had been determined for sporadic ones in the literature. Moreover, this study shows that the positive family history by alone, cannot be the most important and determining indicator of subtelomeric aberrations while it would be a good predicting factor when associated with dysmorphism or congenital malformations. These findings propose that other cryptic chromosomal abnormalities or even single gene disorders may be the main cause of familial ID rather than subtelomeric aberrations. © 2012 Rafati et al; licensee BioMed Central Ltd. Source

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