Genetic Background in Patients with Severe Factor XIII A-Subunit Deficiency Treated with Recombinant FXIII

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1125-1125
Author(s):  
Vytautas Ivaskevicius ◽  
Arijit Biswas ◽  
Anne Thomas ◽  
Ramin Tehranchi ◽  
Johannes Oldenburg
Keyword(s):  
Splice Site ◽  
Factor Xiii ◽  
Splice Site Mutation ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Rt Pcr ◽  
Site Mutation ◽  
B Subunit ◽  
A Subunit ◽  
Fxiii Deficiency

Abstract Abstract 1125 Background and Objectives: Congenital Factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder, with a significant majority of patients showing defects in the FXIII-A subunit. The disease is caused by a variety of F13A1 gene mutations resulting in a severe quantitative FXIII-A type I deficiency. Here, we report a wide spectrum of mutations identified in 41 severe Factor XIII-A deficiency patients (≥6 years of age, mean, 26.4; range, 7–60). Patients and Methods: A total of 41 patients were recruited in a multinational (23 centers, 11 countries), open-label, single-arm, phase 3, prophylaxis trial for the evaluation of the efficacy and safety of a novel recombinant FXIII (rFXIII). Eleven of the 41 patients (Israel [n=8], Switzerland [n=2] and Italy [n=1]) already had established genetic backgrounds and carried previously reported F13A1 mutations. Mutational screening in the remaining 30 patients who had unknown genetic status was done using direct sequencing on an ABI Prism 3130TL (Applied Biosystems, Weiterstadt, Germany). For two patients with splice-site mutations, cDNA analysis was done with RT-PCR (Quiagen One-step RT-PCR kit). The crystallographic model of the recombinant human cellular coagulation FXIIIA zymogen (EC: 2.3.2.13, resolution solved to 2.1Å) was downloaded from the Protein Data Bank (data file 1F13) for viewing, analysis and graphical rendering using YASARAver11.11.2. Classic molecular dynamic simulation approaches were used on the FXIII-A crystal structure to evaluate the effect of the novel missense mutations on protein structure. Results and Discussion: In total, 31 distinct mutations in 41 patients have been identified revealing 13 missense mutations, seven small deletions, six splice-site mutations, three nonsense mutations, one large deletion and one small insertion. Amongst this cohort of mutations, 16 mutations were novel. In one patient, a heterozygous missense mutation was detected in spite of severe deficiency symptoms shown by the patient. We assume that the other mutation could not be detected within the scope of our screening set up. The IVS5–1G>A (c.691–1G>A) splice-site mutation was the most commonly occurring (n=9 [21.9%]) mutation in this cohort. Two siblings carried a missense mutation in F13A1 gene (Ser295Arg) and in combination with a novel variant in F13B gene (Ser634Phe). This variant does not seem to significantly affect the B-subunit stability, since it is located in the terminal part of the molecule. Missense mutations are of special interest since they help to better understand the structure and function of FXIII A-subunit. The MD simulation of four novel missense mutations predicted a damaging effect on the protein structure for three of the missense mutations (Glu229Arg, Leu275Phe, and Arg703Trp) based on changes in bonding patterns, free energy calculations, change in local secondary structure etc. The Leu588Gln located on the surface of barrel 1 domain was not observed to cause a significant change in local structure, nevertheless, owing to its surface presentation it might influence the interaction with FXIII B-subunit. The analysis for the two novel splice-site mutations (IVS7+1G>A, IVS12+1G>A) did not show any aberrant mRNA product. Inhibitor development is the most undesirable side-effect of treatment with plasma-derived or rFXIII products. Overall, the incidence of inhibitors in patients with congenital FXIII deficiency is unknown, but is expected to be much lower compared with other coagulopathies, e.g. hemophilia A. In the present study, none of the patients treated with rFXIII (a mean treatment period of 322 days) developed FXIII neutralizing antibodies. Four patients developed transient low-titer anti-rFXIII antibodies that had no neutralizing activity. Interestingly, two patients (male and female) were siblings carrying the same common splice-site mutation in intron 5 (IVS5-1 G>A). The third patient was compound heterozygous for two missense mutations (Gln229Arg; Ser413Leu). The fourth patient was also found to be compound heterozygous for two missense mutations (Arg77His; Leu275Phe). Conclusion: To conclude, the identified mutations, including 16 novel mutations, are implicated in the causality of severe FXIII deficiency. However, none of these mutations were associated with the development of inhibitory antibodies in the context of treatment with rFXIII. Disclosures: Tehranchi: Novo Nordisk: Employment, Equity Ownership. Oldenburg:Biogen Idec, Swedish Orphan Biovitrum: Honoraria; Baxter, Bayer, Biotest, CSL Behring, Grifols, Inspiration, Novo Nordisk, Octapharma, Pfizer: Honoraria, Research Funding.

Five Novel Mutations in F13B Gene Resulting in FXIII Deficiency.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2150-2150
Author(s):  
Vytautas Ivaskevicius ◽  
Hannelore Rott ◽  
Inge Scharrer ◽  
Manuela Krause ◽  
Erhard Seifried ◽  
...  
Keyword(s):  
Amino Acids ◽  
Disulfide Bond ◽  
Splice Site ◽  
Splice Site Mutation ◽  
Genetic Defects ◽  
Novel Mutations ◽  
Site Mutation ◽  
B Subunit ◽  
Fxiii Activity ◽  
Fxiii Deficiency

Abstract Introduction. FXIII deficiency is a rare autosomal recessive disorder affecting approximatly 1 out of 1–3 million inhabitans. The disease is characterized by bleeding, impaired wound repair and spontaneous abortions in females. Extracellular FXIII molecule has a tetramer structure composing of two catalytic A-subunits and two B-subunits that act as a carrier molecules. Based on genotype there are two types of FXIII deficiency: A-subunit deficiency (XIIIA) when mutations affect F13A gene and much rarely B-subunit deficiency (XIIIB) when mutations affect F13B gene. Both types result in absence of FXIII catalytical activity in plasma. To date, only five families with isolated B-subunit deficiency have been described in the literature. Here we report five novel mutations, affecting F13B gene and resulting in FXIII deficiency. Materials and Methods. FXIII activity was measured by photometric assay according to Fickenscher et al. (1991). Fiveteen exons of F13A gene as well as 12 exons of F13B gene and their flanking regions were amplified by PCR. Sequencing was performed on an automated sequencing system. Results and Discussion. Five german origin patients with mildly reduced FXIII deficiency have been routinely investigated in order to identify genetic defects within F13A and F13B genes. All patients have shown single heterozygous mutations in F13B gene, revealing two missense, one deletion, one insertion, and one splice site mutation. There were no genetic defects in F13A gene. Patient E.M. (female, born 1947, FXIII activity 47–53%, postoperative bleeding) had a missense mutation in exon 2 (c.73 T>C, Cys5Arg) resulting in disruption of disulfide bond between amino acids Cys5 and Cys56. Patient H.D. (male, born 1983, FXIII activity 54%, epistaxis) showed a missense mutation in exon 3 (c.406C>T, Leu116Phe). It may cause instability of disulfide bond between neighbouring Cys117 and Cys71 in the second domain. Patient E.R. (female, born 1989, FXIII activity 53%, increased bleeding during menstruation) was heterozygous for an in-frame deletion (c.471–473delATT) resulting in deletion of Leu138. Patient O.S. (female, born 1983, FXIII activity 46–57%, bleeding after tonsillectomy) had a small insertion (c.1959insT) in the exon 12 changing the distal amino acid (634–641) sequence and predisposing a synthesis of additional 21 new amino acids at the Carboxy-termini of FXIIIB-Subunit due to disruption of Stop codon at position 641. Patient P.G. (male, born 1974, FXIII activity 43%, bleeding after tooth extraction) was heterozygous for a splice site mutation in intron 3 (IVS3-1 G>C). Interestingly this patient turned out also to have a mild von Willebrand Syndrome (FVIII activity 76%, vWF:RiCo 48%, vWF:Ag 56%, vWF-Collagen-Binding activity 0.54, AB0 blood group A). In conclusion, our results suggest higher prevalence of FXIIIB deficiency as it was thought before, Patients having mild (heterozygous) FXIIIB deficiency may bleed upon provocations.

International Registry on Factor XIII Deficiency: A basis formed mostly on European data

2007 ◽  
Vol 97 (06) ◽  
pp. 914-921 ◽  
Author(s):  
Rainer Seitz ◽  
Hans Kohler ◽  
Verena Schroeder ◽  
Laszlo Muszbek ◽  
Robert Ariens ◽  
...  
Keyword(s):  
Haplotype Analysis ◽  
Splice Site Mutation ◽  
Improve Patient Care ◽  
Blood Coagulation Disorders ◽  
Site Mutation ◽  
B Subunit ◽  
International Registry ◽  
A Subunit ◽  
Improve Patient ◽  
Fxiii Deficiency

SummaryFXIII deficiency is known as one of the rarest blood coagulation disorders. In this study, the phenotypic and in part genotypic data of 104 FXIII-deficient patients recorded from 1993 – 2005 are presented. The most common bleeding symptoms were subcutaneous bleeding (57%) followed by delayed umbilical cord bleeding (56%), muscle hematoma (49%), hemorrhage after surgery (40%), hemarthrosis (36%), and intracerebral bleeding (34%). Prophylactic treatment was initiated in about 70% of all patients. FXIII-B subunit-deficient patients had a milder phenotype than patients with FXIII-A subunit deficiency. The most frequent mutation affecting the F13A gene was a splice site mutation in intron 5 (IVS5–1G>A). This mutation was found in eight (17%) of 46 analyzed families. The haplotype analysis of patients carrying the IVS5–1A allele was consistent with a founder effect. The international registry (http://www.f13-database.de) will provide clinicians and scientists working on FXIII deficiency with a helpful tool to improve patient care and direct future studies towards better understanding and treatment of the disease.

A Novel Splice Site Variant in FOXN1 in A Patient with Abnormal Newborn Screening for Severe Combined Immunodeficiency and Congenital Lymphopenia

2021 ◽  
Author(s):  
Ori Scott ◽  
Jenny Garkaby ◽  
Jessica Willett-Pachul ◽  
Yehonatan Pasternak
Keyword(s):  
Splice Site ◽  
Severe Combined Immunodeficiency ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Combined Immunodeficiency ◽  
Site Mutation ◽  
Cd8 Cells ◽  
Cell Counts ◽  
Epithelial Development ◽  
Whole Exome

Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations. Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency. Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation. Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother. Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up.

scholarly journals Predicting Phenotype in Steroid 21-Hydroxylase Deficiency? Comprehensive Genotyping in 155 Unrelated, Well Defined Patients from Southern Germany

2000 ◽  
Vol 85 (3) ◽  
pp. 1059-1065 ◽  
Author(s):  
Nils Krone ◽  
Andreas Braun ◽  
Adelbert Anton Roscher ◽  
Dietrich Knorr ◽  
Hans Peter Schwarz
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Severe Mutation ◽  
Heterozygous Form ◽  
21 Hydroxylase Deficiency ◽  
Intron 2

Abstract Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppvnull) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppvA to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppvB was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppvC was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying 21-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.

A Common Splice Site Mutation Is Shared by Two Families with Different Type 2N von Willebrand Disease Mutations

1999 ◽  
Vol 82 (09) ◽  
pp. 1061-1064 ◽  
Author(s):  
Kingsley Hampton ◽  
F. Eric Preston ◽  
Ian Peake ◽  
Anne Goodeve ◽  
I. Mandy Nesbitt
Keyword(s):  
Splice Site ◽  
Direct Sequencing ◽  
Splice Site Mutation ◽  
Von Willebrand Disease ◽  
The Other ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Disease Mutations ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryUsing an ELISA-based method to detect type 2N von Willebrand disease (VWD), we found two individuals with absent FVIII binding. Direct sequencing of the FVIII binding region of the von Willebrand factor (VWF) gene showed that one individual had an R854Q substitution whilst the other had a T791M substitution. The very low FVIII binding and the VWF:Ag levels in both individuals suggested a second defect on the other VWF allele. Conformation sensitive gel electrophoresis of polymerase chain reaction amplified DNA was used to detect an additional change in the VWF gene of each patient. Direct sequencing confirmed a previously unreported G to A transition in the donor splice site in intron 25 of both individuals which should result in a null allele. This was confirmed by mRNA analysis. These two individuals therefore have compound heterozygous VWD in which the only expressed allele has a type 2N mutation. In our population, such compound heterozygosity appears to be a significant cause of type 2N VWD.

scholarly journals Relationship between HUWE1 Mutation and Functionality in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4512-4512
Author(s):  
Lisa J Crawford ◽  
David Campbell ◽  
Ken I Mills ◽  
Alexandra E Irvine
Keyword(s):  
Multiple Myeloma ◽  
Cell Line ◽  
Cell Lines ◽  
Splice Site ◽  
Mutant Cell ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Mutational Status ◽  
Expression And Activity

Abstract Background Proteasome inhibitors have provided significant therapeutic advance in the treatment of Multiple Myeloma (MM), however resistance and dose limiting side effects remain a clinical challenge. Recent research has focused on developing strategies to target other enzymes within the ubiquitin proteasome system, with the aim of overcoming resistance and toxicity. We have previously reported deregulated expression of the E3 ligase HUWE1 in MM and demonstrated that knockdown or inhibition of HUWE1 leads to a decrease in MYC activity (Blood 2016, 128:240; 2017, 130:3077). HUWE1 is a large HECT domain E3 ligase that is involved in the regulation of key proteins such as p53, MYC and MCL-1. Mutations in HUWE1 have recently been identified in MM patients, significantly associated with the t(11;14) subgroup (blood-2018-03-840132). A recurrently mutated splice site mutation in the DUF913 (domain of unknown function 913) of HUWE1 was identified in 18% of patients, the remainder are predominantly missense mutations distributed across the coding sequence (CDS). Other studies have demonstrated that point mutations in the dimerization interface of HUWE1, which acts to regulate its activity, result in hyper-activation of HUWE1 (eLife 2017;6:e21036; Sci Rep 2017;7:15050). While 7% of the mutations reported in MM patients are found in this region, the effect of the majority of mutations on the functional significance of HUWE1 has yet to be determined. The aim of this study was to analyse HUWE1 expression and activity in HUWE1 mutant MM cell lines. Methods HUWE1 mutational status was analysed in a publically available dataset of MM cell lines (www.keatslab.org). Inhibitors of HUWE1 (BI8622, BI8626; described in EMBO Mol Med 2014, 6:1525-1541) were purchased from Syngene. The effect of the inhibitors on HUWE1 mutant MM cell lines was assessed using CellTitre-glo. HUWE1 auto-ubiquitination activity was analysed using UbiQapture-Q and Western blotting. Results HUWE1 mutations were identified in 6 out of 69 MM cell lines. HUWE1 mutational status was confirmed in 5 cell lines (U266, XG-1, XG-2, KMS-27, H1112) by Sanger sequencing. In agreement with MM patient data, HUWE1 mutations were predominantly found in cell lines expressing the t(11;14) translocation (4/6 cell lines) and are distributed in a similar manner. H1112 cells harbor the recurrent splice site mutation observed in patients, whereas the other cell lines contain missense mutations across the CDS. HUWE1 protein expression in mutant cell lines was compared with expression in 5 MM cell lines expressing wild type (WT) HUWE1 (JJN3, MM.1S, ANBL-6, KMS-18, OPM-2). No significant difference in expression was observed in the majority of HUWE1 mutant cell lines, however, HUWE1 expression was significantly lower in the H1112 cell line (p=0.002) compared to HUWE1 WT cell lines. Accordingly, HUWE1 auto-ubiquitination activity was reduced only in H1112 cells. XG-2 and U266 displayed similar sensitivity to HUWE1 inhibitors as HUWE1 WT cell lines (IC50 12-18 µM vs 9-20 µM), while XG-1, H1112 and KMS-27 were less sensitive (IC50 20-33 µM). The effect of HUWE1 on substrate proteins (e.g. MYC) varies depending on tumor type. In HUWE1 WT MM cell lines, inhibition of HUWE1 leads to significantly decreased expression of MYC and MCL-1 in (p<0.01), through increased proteasomal degradation. A similar decrease in MYC and MCL-1 expression is observed in XG-2, and in MCL-1 in U266 cells (which lack expression of c-MYC). Conversely, no significant effect on MYC or MCL-1 expression was seen in XG-1 cells, while barely detectable levels of MYC and MCL-1 were observed in H1112 and KMS-27 cells, suggesting altered or absent HUWE1 activity in these cell lines. Conclusion HUWE1 has recently been identified as a mutational driver in t(11;14) MM, however, little is known about the functional consequence of HUWE1 mutations. Here we show that the H1112 cell line, representative of the most commonly occurring HUWE1 mutation in MM, leads to reduced expression and activity of HUWE1 and is associated with low expression of HUWE1 substrates MYC and MCL-1. Conversely, expression of HUWE1 and activity against selected substrates remains unchanged in XG-2 and U266 cells. Moreover, recent studies demonstrate that certain HUWE1 mutations lead to enhanced catalytic activity. In summary, the pathogenicity of HUWE1 mutations in MM is likely to depend on the type and location of the mutation. Disclosures No relevant conflicts of interest to declare.

Establishment of an International Registry of Patients with Inherited FXIII Deficiency.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2149-2149
Author(s):  
Vytautas Ivaskevicius ◽  
Rainer Seitz ◽  
Hans P. Kohler ◽  
Laszlo Muszbek ◽  
Robert A.S. Ariens ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Working Party ◽  
Splice Site Mutation ◽  
Autosomal Recessive Disorder ◽  
Bleeding Tendency ◽  
Site Mutation ◽  
Impaired Wound Healing ◽  
Thrombosis Research ◽  
The Impact ◽  
Fxiii Deficiency

Abstract Inherited factor XIII (FXIII) deficiency is a rare autosomal recessive disorder affecting approximately one out of one to three million people. FXIII deficiency is characterized by a lifelong bleeding tendency, impaired wound healing and spontaneous abortions in females. In 1993, the European Thrombosis Research Organization (ETRO) Working Party on FXIII initiated a Europe-wide questionnaire on inherited FXIII deficiency. Since 2005, the registry has been endorsed by the Factor XIII Subcommittee of the Scientific and Standardization committee (SSC) of the ISTH. The analysis of 104 European patients demonstrated that the most common bleeding symptoms were subcutaneous bleeding (57%) followed by delayed umbilical cord bleeding (56%), muscle hematoma (49%), hemorrhage after surgery (40%), hemarthrosis (36%), and intracerebral bleeding (34%). Prophylactic treatment was initiated in about 70% of all patients. FXIII-B subunit-deficient patients had a milder phenotype than patients with FXIII-A subunit deficiency.The most frequent mutation affecting the F13A gene was a splice site mutation in intron 5 (IVS5-1G&gt;A).This mutation was found in eight (17%) of 46 analyzed families.The haplotype analysis of patients carrying the IVS5-1A allele was consistent with a founder effect. Recently, we created a new FXIII database website (http://www.f13-database.de) with information about FXIII proteins, genes, mutations and polymorphisms. This website also includes a new questionnaire. Information provided by this questionnaire will allow better understanding of the differences of diagnostic and treatment possibilities in various parts of the world, and it will help to understand the impact of reduced FXIII activity in heterozygous relatives and finally, it will generally increase our knowledge on this rare disease. We hope that our initiative to establish a new international FXIII registry will be actively supported by the community involved in caring for FXIII deficient patients.

scholarly journals Identification of Missense Mutation Pro77Arg As A Founder Mutation in Morquio-A Syndrome in Indian Gujarati Patel Ethnicity

2020 ◽  
Author(s):  
Jayesh J Sheth ◽  
Riddhi Bhavsar ◽  
Aadhira Nair ◽  
Chandni Patel ◽  
Premal Naik ◽  
...  
Keyword(s):  
Splice Site ◽  
Haplotype Analysis ◽  
Founder Mutation ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Morquio A ◽  
Healthy Control ◽  
Morquio A Syndrome

Abstract Background: Morquio A syndrome (MPS IVA) is a mucopolysaccharide group storage disorder caused due to the deficient activity of the lysosomal enzyme N-acetylgalactoseamine-6-sulfatase encoded by GALNS. The present study represents the mutation spectrum of GALNS in 25 Gujarati Patel patients of India clinically and biochemically confirmed with Morquio-A disorder.Methods: Urinary GAG quantitation and leucocyte enzyme assay was carried out in all 25 patients. This was followed by molecular characterization by amplification and sequencing of the exons and adjacent intronic regions of GALNS gene. Haplotype analysis was performed in patients showing p.P77R variant, using microsatellite markers D16S3121, D16S3026 and D16S3023 and SNPs.Results: We identified 11 mutations that include eight missense mutations: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site mutation: (c.121-7C>G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_41delACA). Of these, three missense mutations (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. In the present study, we found maximum number of mutant alleles in exon 2, and of note, the variant p.P77R was seen in fourteen patients. Conclusion: p.P77R variant was predominantly found in Gujarati Patel community and the results of haplotype analysis indicated it to be the founder mutation in this community. Further, a study of 200 unrelated healthy control participants from Gujarat has identified this mutation in the heterozygous status in two individuals. Overall, our study suggests that p.P77R is likely to be a founder mutation for Morquio-A syndrome in Gujarati Patel ethnicity.

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