Molecular diagnosis of α-thalassemia in a multiethnic population.
OBJECTIVE
α-Thalassemia, one of the most common genetic diseases, is caused by deletions or point mutations affecting one to four α-globin genes. Molecular diagnosis is important to prevent the most severe forms of the disease. However, the diagnosis of α-thalassemia is complex due to a high variability of the genetic defects involved, with over 250 described mutations. We summarize herein the findings of genetic analyses of DNA samples referred to our laboratory for the molecular diagnosis of α-thalassemia, along with a detailed clinical description.


METHODS
We utilized a diagnostic algorithm including Gap-PCR, to detect known deletions, followed by sequencing of the α-globin gene, to identify known and novel point mutations, and multiplex ligation-dependent probe amplification (MLPA) for the diagnosis of rare or novel deletions.


RESULTS
α-Thalassemia was diagnosed in 662 of 975 samples referred to our laboratory. Most commonly found were deletions (75.3%, including two novel deletions previously described by us); point mutations comprised 25.4% of the cases, including five novel mutations. Our population included mostly Jews (of Ashkenazi and Sephardic origin) and Muslim Arabs, who presented with a higher rate of point mutations and hemoglobin H disease. Overall, we detected 53 different genotype combinations causing a spectrum of clinical phenotypes, from asymptomatic to severe anemia.


CONCLUSIONS
Our work constitutes the largest group of patients with α-thalassemia originating in the Mediterranean whose clinical characteristics and molecular basis have been determined. We suggest a diagnostic algorithm that leads to an accurate molecular diagnosis in multiethnic populations.
Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tik, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Oded
http://orcid.org/0000-0002-0033-3425
O
Gilad
Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tik, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.
Orna Steinberg
OS
Shemer
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.
Orly
O
Dgany
Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.
Tanya
T
Krasnov
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tik, Israel.
Michal
M
Nevo
Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.
Sharon
S
Noy-Lotan
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tik, Israel.
Ron
R
Rabinowicz
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tik, Israel.
Nofar
N
Amitai
Bioinformatics and Biological Computing Unit, Weizmann Institute of Science, Rehovot, Israel.
Shifra
S
Ben-Dor
Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tik, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Isaac
I
Yaniv
Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tik, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Joanne
J
Yacobovich
Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tik, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.
Hannah
H
Tamary
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D018912:Arabs; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006447:Hemoglobin H / Q000235:genetics*; D006801:Humans; D007223:Infant; D007557:Israel; D007585:Jews; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods; D010641:Phenotype; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D012720:Severity of Illness Index; D055542:alpha-Globins / Q000737:chemistry / Q000235:genetics*; D017085:alpha-Thalassemia / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics / Q000473:pathology
D055542:alpha-Globins; D006447:Hemoglobin H
microcytic anemia; molecular diagnosis; α-thalassemia