A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects

Fanconi anemia (FA) is a rare autosomal or X‐linked genetic disorder characterized by chromosomal breakages, congenital abnormalities, bone marrow failure (BMF), and cancer. There has been a discovery of 22 FANC genes known to be involved in the FA pathway. This wide number of pathway components mak...

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Published in:	Human mutation Vol. 42; no. 12; pp. 1648 - 1665
Main Authors:	George, Merin, Solanki, Avani, Chavan, Niranjan, Rajendran, Aruna, Raj, Revathi, Mohan, Sheila, Nemani, Sandeep, Kanvinde, Shailesh, Munirathnam, Deendayalan, Rao, Sudha, Radhakrishnan, Nita, Lashkari, Harsha Prasada, Ghildhiyal, Radha Gulati, Manglani, Mamta, Shanmukhaiah, Chandrakala, Bhat, Sunil, Ramesh, Sowmyashree, Cherian, Anchu, Junagade, Pritesh, Vundinti, Babu Rao
Format:	Journal Article
Language:	English
Published:	United States Hindawi Limited 01-12-2021
Subjects:	Anemia Bone marrow chromosomal breakages Complementation complementation groups Diagnosis DNA Helicases FANCA FANCA gene FANCB FANCC FANCC protein FANCD1 FANCD2 FANCE FANCF FANCG FANCG gene FANCI FANCJ FANCL FANCM FANCN FANCO Fanconi anemia Fanconi Anemia - diagnosis Fanconi Anemia - genetics Fanconi Anemia Complementation Group Proteins - genetics Fanconi Anemia Complementation Group Proteins - metabolism Fanconi syndrome FANCP FANCQ FANCR/RAD51 FANCS FANCT FANCU/XRCC2 FANCV/MAD2L2/REV7 FANCW/RFWD3 Gene deletion Genetic disorders genotype–phenotype Humans India Metaphase mutations Next-generation sequencing Patients Skin pigmentation India Fanconi anemia mutations chromosomal breakages FANCQ FANCP FANCS FANCT FANCI complementation groups FANCJ FANCM FANCL FANCO FANCN FANCW/RFWD3 FANCA FANCR/RAD51 FANCC FANCB FANCE genotype-phenotype FANCG FANCF FANCU/XRCC2 FANCD2 FANCD1 FANCV/MAD2L2/REV7
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Summary:	Fanconi anemia (FA) is a rare autosomal or X‐linked genetic disorder characterized by chromosomal breakages, congenital abnormalities, bone marrow failure (BMF), and cancer. There has been a discovery of 22 FANC genes known to be involved in the FA pathway. This wide number of pathway components makes molecular diagnosis challenging for FA. We present here the most comprehensive molecular diagnosis of FA subjects from India. We observed a high frequency (4.42 ± 1.5 breaks/metaphase) of chromosomal breakages in 181 FA subjects. The major clinical abnormalities observed were skin pigmentation (70.2%), short stature (46.4%), and skeletal abnormalities (43.1%), along with a few minor clinical abnormalities. The combination of Sanger sequencing and Next Generation Sequencing could molecularly characterize 164 (90.6%) FA patients and identified 12 different complementation groups [FANCA (56.10%), FANCG (16.46%), FANCL (12.80%), FANCD2 (4.88%), FANCJ (2.44%), FANCE (1.22%), FANCF (1.22%), FANCI (1.22%), FANCN (1.22%), FANCC (1.22%), FANCD1 (0.61%) and FANCB (0.61%)]. A total of 56 novel variants were identified in our cohort, including a hotspot variant: a deletion of exon 27 in the FANCA gene and a nonsense variant at c.787 C>T in the FANCG gene. Our comprehensive molecular findings can aid in the stratification of molecular investigation in the diagnosis and management of FA patients. The combination of Sanger sequencing and Next Generation Sequencing could molecularly characterize 164 (90.6%) FA patients and identified 12 different complementation groups [FANCA (56.10%), FANCG (16.46%), FANCL (12.80%), FANCD2 (4.88%), FANCJ (2.44%), FANCE (1.22%), FANCF (1.22%), FANCI (1.22%), FANCN (1.22%), FANCC (1.22%), FANCD1 (0.61%) and FANCB (0.61%)] including 56 novel variants.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1059-7794 1098-1004
DOI:	10.1002/humu.24286