Characterization of population genetic structure of hereditary transthyretin amyloidosis in Bulgaria

Abstract The hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal dominant genetic disease characterized by amyloid formation in different tissues due to pathogenic variants in the TTR gene. Great heterogeneity in the penetrance and manifestation of ATTRv amyloidosis is observed. In Bulgaria, the most common TTR pathogenic variant is Glu89Gln. Other TTR pathogenic variants are also found – Val30Met, Ser77Phe, Gly47Glu and Ser52Pro. There is a proven founder effect for the Glu89Gln variant, thus the aim of the present study is to investigate the founder effect for the other TTR pathogenic variants in Bulgaria. Haplotype analysis was performed by using microsatellite markers close to the TTR gene. DNA samples from ATTRv amyloidosis patients and their healthy relatives were analyzed. Theoretical haplotype reconstruction was done with Arlequin v.3.01 software. The age of the most recent common ancestor (hypothetical founder) for the studied variants was calculated with the DMLE 2.2 software. In addition, DBS screening among 100 Roma newborns was done for the Gly47Glu TTR variant via direct Sanger sequencing. The reconstructed haplotypes of the patients were compared to their healthy relatives and to a control group of 40 healthy individuals. The results showed a possible founder effect for each of the studied variants. The Val30Met haplotype was compared to published haplotype data for this variant and no similarity was found. The result from the DBS screening showed no pathogenic TTR variants in exon 2 of the gene, so we considered the presence of the Gly47Glu variant in our population a sporadic event. With this study, we succeeded to gain a more complete picture of the population genetics of ATTRv amyloidosis in Bulgaria and made another step towards a more detailed understanding of the disease epidemiology.

[1]  M. Sabatelli,et al.  Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care , 2020, Therapeutics and clinical risk management.

[2]  V. Mitev,et al.  Founder effect of the Glu89Gln TTR mutation in the Bulgarian population , 2019, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[3]  M. Slama,et al.  Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease , 2019, Nature Reviews Neurology.

[4]  V. P. Costa,et al.  Estimating the age of the p.Cys433Arg variant in the MYOC gene in patients with primary open-angle glaucoma , 2018, PloS one.

[5]  P. Oliveira,et al.  mtDNA copy number associated with age of onset in familial amyloid polyneuropathy , 2017, Journal of Neurology, Neurosurgery, and Psychiatry.

[6]  A. Sousa,et al.  A Trans-acting Factor May Modify Age at Onset in Familial Amyloid Polyneuropathy ATTRV30M in Portugal , 2017, Molecular Neurobiology.

[7]  Y. Parman,et al.  Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey , 2016, Neuromuscular Disorders.

[8]  David Adams,et al.  Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP , 2016, Current opinion in neurology.

[9]  T. Todorov,et al.  Epidemiology of Familial Amyloid Polyneuropathy in Bulgaria , 2015, Orphanet Journal of Rare Diseases.

[10]  G. Vita,et al.  TTR-FAP: a single-center experience in Sicily, an Italian endemic area , 2015, Orphanet Journal of Rare Diseases.

[11]  A. Mauro,et al.  Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation , 2015, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[12]  P. Hawkins,et al.  Online Registry for Mutations in Hereditary Amyloidosis Including Nomenclature Recommendations , 2014, Human mutation.

[13]  R. Polimanti,et al.  Functional variation of the transthyretin gene among human populations and its correlation with amyloidosis phenotypes , 2013, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[14]  Yukio Ando,et al.  Guideline of transthyretin-related hereditary amyloidosis for clinicians , 2013, Orphanet Journal of Rare Diseases.

[15]  F. Salvi,et al.  Genotypic and phenotypic correlation in an Italian population of hereditary amyloidosis TTR-related (HA-TTR): clinical and neurophysiological aids to diagnosis and some reflections on misdiagnosis , 2012, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[16]  C. Bonaïti‐pellié,et al.  TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance? , 2010, European Journal of Human Genetics.

[17]  P. Galle,et al.  Liver transplantation and combined liver‐heart transplantation in patients with familial amyloid polyneuropathy: A single‐center experience , 2010, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[18]  K. Ono,et al.  Epidemiology of familial amyloid polyneuropathy in Japan: Identification of a novel endemic focus , 2008, Journal of the Neurological Sciences.

[19]  E. Génin,et al.  On the Origin of the Transthyretin Val30Met Familial Amyloid Polyneuropathy , 2008, Annals of human genetics.

[20]  Montgomery Slatkin,et al.  Linkage disequilibrium — understanding the evolutionary past and mapping the medical future , 2008, Nature Reviews Genetics.

[21]  P. Radice,et al.  Reconstructing the Genealogy of a BRCA1 Founder Mutation by Phylogenetic Analysis , 2008, Annals of human genetics.

[22]  C. Bonaiti-Pellié,et al.  Heterogeneity of penetrance in familial amyloid polyneuropathy, ATTR Val30Met, in the Swedish population , 2008, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[23]  Laurent Excoffier,et al.  Arlequin (version 3.0): An integrated software package for population genetics data analysis , 2005, Evolutionary bioinformatics online.

[24]  T. Nakajima,et al.  Common origin of the Val30Met mutation responsible for the amyloidogenic transthyretin type of familial amyloidotic polyneuropathy , 2004, Journal of Medical Genetics.

[25]  B. Hazenberg,et al.  Familial amyloidotic polyneuropathy with severe renal involvement in association with transthyretin Gly47Glu in Dutch, British and American-Finnish families , 2004, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[26]  G. Sobue,et al.  Type I (transthyretin Met30) familial amyloid polyneuropathy in Japan: early- vs late-onset form. , 2002, Archives of neurology.

[27]  Bruce Rannala,et al.  DMLE+: Bayesian linkage disequilibrium gene mapping , 2002, Bioinform..

[28]  A. Pizzi,et al.  Familial amyloid polyneuropathy with genetic anticipation associated to a gly47glu transthyretin variant in an Italian kindred , 2002, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[29]  A. Sousa,et al.  Genetic epidemiology of familial amyloidotic polyneuropathy (FAP)-type I in Póvoa do Varzim and Vila do Conde (north of Portugal). , 1995, American journal of medical genetics.

[30]  A. Sousa,et al.  A study of 159 Portuguese patients with familial amyloidotic polyneuropathy (FAP) whose parents were both unaffected. , 1994, Journal of medical genetics.

[31]  G. Holmgren,et al.  Familial amyloidotic polyneuropathy in Sweden: geographical distribution, age of onset, and prevalence. , 1993, Human heredity.