Molecular Pathology of Rare Bleeding Disorders (RBDs) in India: A Systematic Review

Abstract

BackgroundThough rare in occurrence, patients with rare bleeding disorders (RBDs) are highly heterogeneous and may manifest with severe bleeding diathesis. Due to the high rate of consanguinity in many caste groups, these autosomal recessive bleeding disorders which are of rare occurrence in populations across the world, may not be as rare in India.ObjectivesTo comprehensively analyze the frequency and nature of mutations in Indian patients with RBDs.MethodsPubmed search was used (www.pubmed.com) to explore the published literature from India on RBDs using the key words “rare bleeding disorders”, “mutations”, “India”, “fibrinogen”, “afibrinogenemia”, “factor II deficiency”, “prothrombin” “factor VII deficiency”, “factor V deficiency”, “factor X deficiency”, “factor XI deficiency”, “combined factor V and VIII deficiency”, “factor XIII deficiency”, “Bernard Soulier syndrome” and “Glanzmanns thrombasthenia” in different combinations. A total of 60 relevant articles could be retrieved. The distribution of mutations from India was compared with that of the world literature by referring to the Human Gene Mutation Database (HGMD) (www.hgmd.org).ResultsTaken together, 181 mutations in 270 patients with different RBDs have been reported from India. Though the types of mutations reported from India and their percentage distribution with respect to the world data are largely similar, yet much higher percentage of small deletions, duplication mutations, insertions, indels were observed in this analysis. Besides the identification of novel mutations and polymorphisms, several common mutations have also been reported, which will allow to develop a strategy for mutation screening in Indian patients with RBDs.ConclusionThere is a need for a consortium of Institutions working on the molecular pathology of RBDs in India. This will facilitate a quicker and cheaper diagnosis of RBDs besides its utility in first trimester prenatal diagnosis of the affected families.

Diagnosis of factor XIII deficiency

“…29,[63][64][65] This common mutation was also observed in India. 66 Arg326Gln FXIII-A gene mutation has been detected in patients from Germany and the Netherlands. 58,67 Thus, in patients with European origin, these three mutations can be selected as the first step in molecular diagnosis of FXIIID.…”

Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders

“…Our literature review identified a large number of novel mutations accounting for congenital fibrinogen disorders, both quantitative [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] and qualitative. [65][66][67][68][69][70][71][72][73][74][75][76] The majority of dysfibrinogenemias, inherited as a dominant trait, are caused by heterozygous missense mutations in one of the three fibrinogen genes.…”

Second trimester prenatal diagnosis in Glanzmann's Thrombasthenia

“…Glanzmann's Thrombasthenia (GT) is a rare (1: 1 000 000) congenital bleeding disorder caused by dysfunctional or absent platelet integrin aIIbb3, because of mutations in the ITGA2B and ITGB3 genes located on chromosome 17q21-23 [1]. The clinical manifestations are highly heterogenous, which include mucocutaneous bleeding such as epistaxis, gum bleeding, haematuria, menorrhagia and gastrointestinal bleed resulting in major morbidity and mortality in affected families.…”

“…The mutations which cause GT are spread all over the ITGA2B and ITGB3 genes. More than 200 mutations have been reported from across the world, which mainly comprise of deletions, point mutations, inversions, insertions and splice site variations, along with large number of polymorphisms [1]. The data published from Indian studies shows 47 unique mutations in 102 GT patients, while in 27 patients, mutation could not be detected despite scanning the entire coding, splice site and the regulatory regions of both the genes [1,3,4].…”

“…More than 200 mutations have been reported from across the world, which mainly comprise of deletions, point mutations, inversions, insertions and splice site variations, along with large number of polymorphisms [1]. The data published from Indian studies shows 47 unique mutations in 102 GT patients, while in 27 patients, mutation could not be detected despite scanning the entire coding, splice site and the regulatory regions of both the genes [1,3,4]. This along with widespread molecular heterogeneity of mutations pose a major hurdle in offering first trimester prenatal diagnosis to the affected families, though it is a safer method over second trimester diagnosis, where the risk of bleeding through cord puncture site could be higher [5].…”