Isfahan University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Autozygosity-Driven Genetic Diagnosis in Consanguineous Families From Italy and the Greater Middle East Publisher Pubmed



Palombo F1, 2 ; Graziano C1 ; Al Wardy N3 ; Nouri N4, 5 ; Marconi C6 ; Magini P1 ; Severi G1 ; La Morgia C2, 7 ; Cantalupo G8, 9 ; Cordelli DM6, 10 ; Gangarossa S11 ; Al Kindi MN3 ; Al Khabouri M3, 12 ; Salehi M4 Show All Authors
Authors
  1. Palombo F1, 2
  2. Graziano C1
  3. Al Wardy N3
  4. Nouri N4, 5
  5. Marconi C6
  6. Magini P1
  7. Severi G1
  8. La Morgia C2, 7
  9. Cantalupo G8, 9
  10. Cordelli DM6, 10
  11. Gangarossa S11
  12. Al Kindi MN3
  13. Al Khabouri M3, 12
  14. Salehi M4
  15. Giorgio E13
  16. Brusco A13
  17. Pisani F14
  18. Romeo G6
  19. Carelli V2, 7
  20. Pippucci T1
  21. Seri M1, 6
Show Affiliations
Authors Affiliations
  1. 1. Medical Genetics Sant’Orsola, Malpighi University Hospital of Bologna, Via Massarenti 9, Bologna, 40138, Italy
  2. 2. IRCCS Istituto Delle Scienze Neurologiche Di Bologna, UOC Clinica Neurologica, Bologna, Italy
  3. 3. Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
  4. 4. Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
  5. 5. Craniofacial and Cleft Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  6. 6. Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
  7. 7. Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
  8. 8. Child Neuropsychiatry, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
  9. 9. UOC Neuropsichiatria Infantile, DAI Materno-Infantile, AOUI Verona, Verona, Italy
  10. 10. Neuropsychiatry Sant’Orsola-Malpighi University Hospital of Bologna, Bologna, Italy
  11. 11. ASP7 Ragusa, Ragusa, Italy
  12. 12. Department of ENT, Al Nahdha Hospital, Ministry of Health, Muscat, Oman
  13. 13. Department of Medical Sciences, University of Torino, Turin, Italy
  14. 14. Child Neuropsychiatry Unit, Department of Medicine & Surgery, University of Parma, Parma, Italy

Source: Human Genetics Published:2020


Abstract

Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low. Nonetheless, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with suspected recessive diseases, 29 originated in GME countries and 18 of Italian descent. We performed autozygosity-driven exome analysis by detecting long runs of homozygosity (ROHs > 1.5 Mb) and by prioritizing candidate clinical variants within. We identified a pathogenic synonymous variant that had been previously missed in NARS2 and we increased an initial high diagnostic rate (47%) to 55% by matchmaking our candidate genes and including in the analysis shorter ROHs that may also happen to be autozygous. GME and Italian families contributed to diagnostic yield comparably. We found no significant difference either in the extension of the autozygous genome, or in the distribution of candidate clinical variants between GME and Italian families, while we showed that the average autozygous genome was larger and the mean number of candidate clinical variants was significantly higher (p = 0.003) in mutation-positive than in mutation-negative individuals, suggesting that these features influence the likelihood that the disease is autozygosity-related. We highlight the utility of autozygosity-driven genomic analysis also in countries and/or communities, where consanguinity is not widespread cultural tradition. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
Related Docs
View other Related Docs
1. Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only, Biomolecules (2023)
2. Clinical and Genetic Profile of Children With Unexplained Intellectual Disability/Developmental Delay and Epilepsy, Epilepsy Research (2021)
3. Homozygosity Mapping and Direct Sequencing Identify a Novel Pathogenic Variant in the Cisd2 Gene in an Iranian Wolfram Syndrome Family, Acta Diabetologica (2020)
4. Familial Nonmedullary Thyroid Cancer: A Case Series in Iranian Patients With a Meta-Review of Case Series, Lab Medicine (2024)
5. Next-Generation Sequencing Reveals a Novel Pathogenic Variant in the Atm Gene, International Journal of Neuroscience (2022)
6. Griscelli Syndrome Type 1: A Novel Pathogenic Variant, and Review of Literature, Molecular Genetics and Genomics (2023)
7. Whole-Exome Sequencing Identifies a Recurrent Small In-Frame Deletion in Myo15a Causing Autosomal Recessive Nonsyndromic Hearing Loss in 3 Iranian Pedigrees, Lab Medicine (2022)
8. Next-Generation Sequencing Reveals a Novel Pathological Mutation in the Tmc1 Gene Causing Autosomal Recessive Non-Syndromic Hearing Loss in an Iranian Kindred, International Journal of Pediatric Otorhinolaryngology (2019)
Experts (# of related papers)
View all Related Experts
Mohammad Amin Tabatabaiefar (34)
Majid Kheirollahi (5)
Other Related Docs
9. A Novel Pathogenic Variant in Naglu (N-Acetyl-Alpha-Glucosaminidase) Gene Identified by Targeted Next-Generation Sequencing Followed by in Silico Analysis, Iranian Journal of Child Neurology (2019)
10. Genotypes of European and Iranian Patients With Type 3 Von Willebrand Disease Enrolled in 3Winters-Ips, Blood Advances (2021)
11. Exome-First Approach Identified Novel Homozygous Dedicator of Cytokinesis 8 (Dock8) Mutations in Three Unrelated Iranian Pedigrees Suspected With Hyper-Ige Syndrome, Iranian Journal of Allergy, Asthma and Immunology (2020)
12. Proband-Only Exome Sequencing for Intellectual Disability in Iran: Diagnostic Yield and Genetic Insights, American Journal of Medical Genetics, Part A (2024)
13. A Homozygous Nonsense Variant in Uvssa Causes Uv‑Sensitive Syndrome From Very Large Kindred: The First Report From Iran, Advanced Biomedical Research (2023)
14. Two Distinct Deleterious Causative Variants in a Family With Multiple Cancer-Affected Patients, Advanced Biomedical Research (2023)
15. Decreased Expression of Hsa-Mir-142-3P and Hsa-Mir-155-5P in Common Variable Immunodeficiency and Involvement of Their Target Genes and Biological Pathways, Allergologia et Immunopathologia (2025)
16. Clinical, Immunologic, and Genetic Spectrum of 696 Patients With Combined Immunodeficiency, Journal of Allergy and Clinical Immunology (2018)
17. A Novel Homozygote Pathogenic Variant in the Diaph1 Gene Associated With Seizures, Cortical Blindness, and Microcephaly Syndrome (Scbms): Report of a Family and Literature Review, Molecular Genetics and Genomic Medicine (2024)
18. Mutation Analysis of Gjb2 and Gjb6 Genes and Screening of Nine Common Dfnb Loci in Iranian Pedigrees With Autosomal Recessive Nonsyndromic Hearing Loss, Indian Journal of Otology (2019)
19. Genetic Linkage Analysis of Dfnb40 and Dfnb48 Loci in Families With Autosomal Recessive Non-Syndromic Hearing Loss (Arnshl) From Western Provinces of Iran, Journal of Isfahan Medical School (2016)
20. Molecular and Phenotypical Findings of a Novel De Novo Syngap1 Gene Variant in an 11-Year-Old Iranian Boy With Intellectual Disability, Lab Medicine (2024)
21. Screening of 10 Dfnb Loci Causing Autosomal Recessive Non-Syndromic Hearing Loss in Two Iranian Populations Negative for Gjb2 Mutations, Iranian Journal of Public Health (2019)
22. Whole Exome Sequencing Identifies Novel Compound Heterozygous Pathogenic Variants in the Myo15a Gene Leading to Autosomal Recessive Non-Syndromic Hearing Loss, Molecular Biology Reports (2020)
23. Consanguineous Marriages in the Genetic Counseling Centers of Isfahan and the Ethical Issues of Clinical Consultations, Journal of Medical Ethics and History of Medicine (2017)
24. Whole Exome Sequencing Revealed a Novel Gjb1 Pathogenic Variant and a Rare Bscl2 Mutation in Two Iranian Large Pedigrees With Multiple Affected Cases of Charcot-Marie-Tooth, International Journal of Molecular and Cellular Medicine (2019)
25. Using Whole Exome Sequencing in Determining the Genetic Cause of Parkinson Disease in an Iranian Family, Neurology Asia (2021)
26. Identification of Pros1 As a Novel Candidate Gene for Juvenile Retinitis Pigmentosa, International Journal of Molecular and Cellular Medicine (2019)
27. Novel Melanocortin-3 and -4 Receptor Functional Variants in Asian Children With Severe Obesity, Journal of Clinical Endocrinology and Metabolism (2024)
28. Novel In-Frame Duplication Variant Characterization in Late Infantile Metachromatic Leukodystrophy Using Whole-Exome Sequencing and Molecular Dynamics Simulation, PLoS ONE (2023)
29. B-Cells Absence in Patients Diagnosed As Inborn Errors of Immunity: A Registry-Based Study, Immunogenetics (2024)
30. An Update of Spectrum and Frequency of Gjb2 Mutations Causing Hearing Loss in the South of Iran: A Literature Review, International Journal of Pediatric Otorhinolaryngology (2019)
31. Mutations in Gjb2 As Major Causes of Autosomal Recessive Non-Syndromic Hearing Loss: First Report of C.299-300Delat Mutation in Kurdish Population of Iran, Journal of Audiology and Otology (2019)
32. Genetic Screening in Adolescents With Steroid-Resistant Nephrotic Syndrome, Kidney International (2013)
33. A Novel Heterozygous Truncating Variant in the Ago1 Gene in an Iranian Family With Schizophrenia As an Unreported Symptom, Annals of Human Genetics (2023)
34. Biallelic Variants in the Ectonucleotidase Entpd1 Cause a Complex Neurodevelopmental Disorder With Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia, Annals of Neurology (2022)
35. In Silico Post Genome-Wide Association Studies Analysis of C-Reactive Protein Loci Suggests an Important Role for Interferons, Circulation: Cardiovascular Genetics (2015)
36. Targeted Next Generation Sequencing Reveals Genetic Defects Underlying Inherited Retinal Disease in Iranian Families, Molecular Vision (2019)
37. Whole-Transcriptome Sequencing–Based Concomitant Detection of Viral and Human Genetic Determinants of Cutaneous Lesions, JCI Insight (2022)
38. A Novel Missense Mutation in Gipc3 Causes Sensorineural Hearing Loss in an Iranian Family Revealed by Targeted Next-Generation Sequencing, International Journal of Pediatric Otorhinolaryngology (2018)
39. Molecular Diagnosis of Slc26a4-Related Hereditary Hearing Loss in a Group of Patients From Two Provinces of Iran, Intractable and Rare Diseases Research (2021)
40. Association of Ahsg With Alopecia and Mental Retardation (Apmr) Syndrome, Human Genetics (2017)
41. A Novel Pathogenic Variant in an Iranian Ataxia Telangiectasia Family Revealed by Next-Generation Sequencing Followed by in Silico Analysis, Journal of the Neurological Sciences (2017)
42. Possible Dual Contribution of a Novel Gucy2d Mutation in the Development of Retinal Degeneration in a Consanguineous Population, European Journal of Medical Genetics (2020)
43. Fourth Update on the Iranian National Registry of Primary Immunodeficiencies: Integration of Molecular Diagnosis, Journal of Clinical Immunology (2018)
44. A Novel Deletion Mutation in Gucy2d Gene May Be Responsible for Leber Congenital Amaurosis-1 Disease: A Case Report, Journal of Current Ophthalmology (2019)
45. Evaluation of Common Col2a1 Gene Variants in Iranian Patients Suspected With Stickler Syndrome Type I, Journal of Research in Medical Sciences (2025)
46. A Novel Mettl5 Variant Disrupting a Donor Splice Site Leads to Primary Microcephaly-Related Intellectual Disability in an Iranian Family: Clinical Features and Literature Review, Journal of Genetics (2023)
47. Clinical and Molecular Assessment of Iranian Families With Severe Congenital Neutropenia, Identification of Hyou1 and Shoc2 As Potential Novel Gene Defects, Iranian Journal of Allergy, Asthma and Immunology (2022)
48. A Novel Pathogenic Variant in the Cabp2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family, Audiology and Neurotology (2019)
49. Mutation Analysis of Slc20a2 and Spp2 As Candidate Genes for Familial Idiopathic Basal Ganglia Calcification, Avicenna Journal of Medical Biotechnology (2013)
50. The Identification of Two Pathogenic Variants in a Family With Mild and Severe Forms of Developmental Delay, Journal of Human Genetics (2021)