J Pediatr Endocr Met 2015; 28(3-4): 421–424
Çiğdem Seher Kasapkara*, Melek Akar, Mehmet Nuri Özbek, Heybet Tüzün, Bedri Aldudak, Rıza Taner Baran and Tijen Tanyalçın
Mutations in BTD gene causing biotinidase deficiency: a regional report Abstract: Biotinidase deficiency is an autosomal recessive inborn error of biotin metabolism. Children with biotinidase deficiency cannot cleave biocytin and, therefore, cannot recycle biotin. Untreated individuals become secondarily biotin deficient, which in turn results in decreased activities of the biotin-dependent carboxylases and the subsequent accumulation of toxic metabolites causing clinical symptoms. Biotinidase deficiency is characterized by neurological, cutaneous manifestations and metabolic abnormalities. The worldwide incidence of profound biotinidase deficiency has been estimated at 1:112,271. The human biotinidase gene is located on chromosome 3p25 and consists of four exons with a total length of 1629 base pairs. To date, more than 100 mutations in the biotinidase gene known to cause biotinidase deficiency have been reported. The vast majority of mutations are homozygous or compound heterozygous. Finding known mutations can be correlated with the biochemical enzymatic results. This report summarizes the demographic features of patients identified as biotinidase deficient from August of 2012 through August of 2013 and mutation analysis results for 20 cases in the southeast region of Turkey. Keywords: biotinidase deficiency; molecular analysis; newborn screening. DOI 10.1515/jpem-2014-0056 Received February 12, 2014; accepted October 22, 2014; previously published online November 25, 2014
*Corresponding author: Dr. Çiğdem Seher Kasapkara, Department of Pediatric Metabolism and Nutrition, Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey, E-mail: [email protected] Melek Akar and Heybet Tüzün: Department of Neonatology, Diyarbakır Children’s Hospital, Diyarbakır, Turkey Mehmet Nuri Özbek and Rıza Taner Baran: Department of Pediatric Endocrinology, Diyarbakır Children’s Hospital, Diyarbakır, Turkey Bedri Aldudak: Department of Cardiology, Diyarbakır Children’s Hospital, Diyarbakır, Turkey Tijen Tanyalçın: Department of Biochemistry, İzmir, Turkey
Introduction Biotin, an essential water-soluble B vitamin that cannot be endogenously synthesized in mammals and that is obtained by means of dietary sources, is the coenzyme for carboxylases in humans. The holocarboxylases are degraded proteolytically to biocytin, which is then cleaved by biotinidase releasing biotin for reutilization, thereby completing the biotin cycle. Biotinidase deficiency (BD) is inherited as an autosomal recessive trait (1, 2). Children with BD cannot cleave biocytin and, therefore, cannot recycle biotin. Untreated individuals become secondarily biotin deficient, which in turn results in decreased activities of the biotindependent carboxylases and the subsequent accumulation of toxic metabolites causing clinical symptoms (3). BD is characterized by neurological and cutaneous manifestations and metabolic abnormalities. Neurological symptoms of BD commonly include myoclonic seizures, ataxia, hypotonia, hearing loss, optic atrophy, and developmental delay. Non-neurological manifestations include alopecia, skin rash, and fungal infection due to reduced cellular immunity (4). Individuals with A, c.557G > A, c.1330G > C, c1368A > C, c1489C > T, and c1595C > T mutations in exon 4 in individuals with BD. We identified c. 470G > A (R157H) homozygous mutation in two patients with partial BD. The majority of the mutations detected in our study population comprised c. 470G > A (R157H) homozygous mutation in exon 4. A singlebase substitution, c. 470G > A (R157H), was observed in 10 patients (eight homozygous and two compound heterozygous). Two of the other mutations detected in more than one patient, c. 235C > T (p.R79C) and c. 1595C > T(p.T532M), were relatively common among patients with BD (Table 1).
Table 1 Biotinidase activity and mutation analysis results for 20 cases of BTD. Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Sex M M F F M F M M F M F F F M M M F M M F
Biotinidase activity, eu
Allele 1
Allele 2
0 10 14 14 0 0 6 11 28 18 0 22 8 15 0 0 29 0 1 24
c.235C > T c.235C > T c.1368A > C c.470G > A c.1595C > T c.1595C > T c. 470G > A c.1595C > T c.470 G > A c.470G > A c.557G > A c.470G > A c.1595C > T c.470G > A c.235C > T c.1330G > C c.470G > A c.235C > T c.470G > A c.470G > A
c.235C > T c.470G > A c.1368A > C c.470G > A c.1595C > T c.1595C > T c. 470G > A c.1595C > T c.470G > > A c.470G > A c.557G > A c.470G > A c.1595C > T c.1489C > T c.235C > T c.1330G > C c.470G > A c.235C > T c.470G > A c.470G > A
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Kasapkara et al.: Mutations in BTD gene causing biotinidase deficiency 423
Discussion Common symptoms of profound BD are presented during the first days of neonatal life and seldom during the first year. All the detected cases were asymptomatic except three of those and supplemented with biotin. Neonatal screening for BD is conducted in our country but not conducted properly because of parents’ noncompliance in the southeast part of Turkey. Therefore, the patients were rather old at the time of diagnosis. Individuals with untreated BD usually develop seizures, hypotonia, skin rash, alopecia, vision problems, hearing loss, and developmental delay with ketolactic acidosis and organic aciduria. Biotinidase enzyme catalyzes the release of biotin from breakdown products of carboxylases and, therefore, plays a crucial role in biotin recycling. Mutations in the BTD gene impair the recycling of biotin and lead to a substantial urinary loss of biotin in forms of biotinylated peptides (10–13). Sensorineural hearing loss in BD occurs in as many as 76% of individuals with symptoms. Hearing loss, visual abnormalities, and developmental delay are usually not reversible with administration of pharmacological doses of biotin (5–20 mg/day) (1). Therefore, it is important that BD is diagnosed early so that biotin therapy can be initiated before permanent neurological damage occurs (14, 15). Many countries including our country screen for this disorder at birth because early treatment with pharmacological doses of biotin can prevent the disorder from becoming symptomatic in children. We are now reporting mutations that cause BD. Newborn screening has enabled identification of children with profound and partial BD (16–18). However, in some cases, enzymatic activity does not adequately differentiate partial deficiency from heterozygosity for profound deficiency; therefore, mutation analysis is necessary to confirm the diagnosis (19). Because of the high rate of consanguinity in the southeastern part of Turkey, all children were the products of consanguineous mating, and all of the children were homozygous or compound heterozygous for specific mutations (c.235C > T in exon 2 and c.470G > A, c.557G > A, c.1330G > C, c1368A > C, c1489C > T, and c1595C > T mutations in exon 4) known to cause profound BD. This disorder remains one of the most preventable causes of mental retardation, vision problems, and hearing loss if diagnosed and treated with biotin before symptoms develop. Identifying the full spectrum of mutations that cause BD will undoubtedly be useful in determining the functional domains of the enzyme. Second-tier mutation analysis also provides valuable support to the enzymatic analysis and should be considered as a supplement to the biochemical data by those performing newborn screening
for BD. Newborn screening allows early presymptomatic treatment that can prevent neurological impairment (20– 22). In conclusion, we determined the mutation spectrum causing partial and profound BD in patients from the southeastern part of Turkey.
References 1. Sivri HS, Genç GA, Tokatli A, Dursun A, Coşkun T, et al. Hearing loss in biotinidase deficiency: genotype-phenotype correlation. J Pediatr 2007;150:439–42. Erratum in: J Pediatr 2007;151:222. 2. Milánkovics I, Kámory E, Csókay B, Fodor F, Somogyi C, et al. Mutations causing biotinidase deficiency in children ascertained by newborn screening in Western Hungary. Mol Genet Metab 2007;90:345–8. 3. Neto EC, Schulte J, Rubim R, Lewis E, DeMari J, et al. Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations. Braz J Med Biol Res 2004;37:295–9. 4. Dobrowolski SF, Angeletti J, Banas RA, Naylor EW. Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency. Mol Genet Metab 2003;78:100–7. 5. Wolf B, Jensen K, Hüner G, Demirkol M, Baykal T, et al. Seventeen novel mutations that cause profound biotinidase deficiency. Mol Genet Metab 2002;77:108–11. 6. Wolf B. Children with profound biotinidase deficiency should be treated with biotin regardless of their residual enzyme activity or genotype. Eur J Pediatr 2002;161:167–8; author reply 169. 7. Pettit DA, Amador PS, Wolf B. The quantitation of biotinidase activity in dried blood spots using microtiter transfer plates: identification of biotinidase-deficient and heterozygous individuals. Anal Biochem 1989;179:371–4. 8. Hymes J, Stanley CM, Wolf B. Mutations in BTD causing biotinidase deficiency. Hum Mutat 2001;18:375–81. 9. Blanton SH, Pandya A, Landa BL, Javaheri R, Xia X, et al. Fine mapping of the human biotinidase gene and haplotype analysis of five common mutations. Hum Hered 2000;50:102–11. 10. Pomponio RJ, Hymes J, Reynolds TR, Meyers GA, Fleischhauer K, et al. Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. Pediatr Res 1997;42:840–8. 11. Pomponio RJ, Reynolds TR, Mandel H, Admoni O, Melone PD, et al. Profound biotinidase deficiency caused by a point mutation that creates a downstream cryptic 3′ splice acceptor site within an exon of the human biotinidase gene. Hum Mol Genet 1997;6:739–45. 12. Pomponio RJ, Narasimhan V, Reynolds TR, Buck GA, Povirk LF, et al. Deletion/insertion mutation that causes biotinidase deficiency may result from the formation of a quasipalindromic structure. Hum Mol Genet 1996;5:1657–61. 13. Procter M, Wolf B, Crockett DK, Mao R. The Biotinidase Gene Variants Registry: a paradigm public database. G3: Genes | Genomes | Genetics 2013;3. Published online at April 2013. doi:pii: g3.113.005835v1. 10.1534/g3.113.005835. 14. Iqbal F, Item CB, Vilaseca MA, Jalan A, Mühl A, et al. The identification of novel mutations in the biotinidase gene using denatur-
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424 Kasapkara et al.: Mutations in BTD gene causing biotinidase deficiency ing high pressure liquid chromatography (dHPLC). Mol Genet Metab 2010;100:42–5. 15. Chedrawi AK, Ali A, Al Hassnan ZN, Faiyaz-Ul-Haque M, Wolf B. Profound biotinidase deficiency in a child with predominantly spinal cord disease. J Child Neurol 2008;23:1043–8. 16. Thodi G, Schulpis KH, Molou E, Georgiou V, Loukas YL, et al. High incidence of partial biotinidase deficiency cases in newborns of Greek origin. Gene 2013;524:361–2. 17. Tiar A, Mekki A, Nagara M, Rhouma FB, Messaoud O, et al. Biotinidase deficiency: novel mutations in Algerian patients. Gene. 2014;536(1):193–6. doi:pii: S0378-1119(13)00185-6. 10.1016/j. gene.2013.02.011.
18. Afroze B, Wasay M. Biotinidase deficiency in Pakistani children; what needs to be known and done. J Pak Med Assoc 2012;62:312–3. 19. Cowan TM, Kazerouni NN, Dharajiya N, Lorey F, Roberson M, et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab 2012;106:485–7. 20. Zempleni J, Kuroishi T. Biotin. Adv Nutr 2012;3:213–4. 21. Hayati AA, Wan-Hitam WH, Cheong MT, Yunus R, Shatriah I. Optic neuritis in a child with biotinidase deficiency: case report and literature review. Clin Ophthalmol 2012;6:389–95. 22. Küry S, Ramaekers V, Bézieau S, Wolf B. Clinical utility gene card for: biotinidase deficiency. Eur J Hum Genet 2012;20. doi: 10.1038/ejhg.2012.28.
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Çiğdem Seher Kasapkara*, Melek Akar, Mehmet Nuri Özbek, Heybet Tüzün, Bedri Aldudak, Rıza Taner Baran and Tijen Tanyalçın
Mutations in BTD gene causing biotinidase deficiency: a regional report Abstract: Biotinidase deficiency is an autosomal recessive inborn error of biotin metabolism. Children with biotinidase deficiency cannot cleave biocytin and, therefore, cannot recycle biotin. Untreated individuals become secondarily biotin deficient, which in turn results in decreased activities of the biotin-dependent carboxylases and the subsequent accumulation of toxic metabolites causing clinical symptoms. Biotinidase deficiency is characterized by neurological, cutaneous manifestations and metabolic abnormalities. The worldwide incidence of profound biotinidase deficiency has been estimated at 1:112,271. The human biotinidase gene is located on chromosome 3p25 and consists of four exons with a total length of 1629 base pairs. To date, more than 100 mutations in the biotinidase gene known to cause biotinidase deficiency have been reported. The vast majority of mutations are homozygous or compound heterozygous. Finding known mutations can be correlated with the biochemical enzymatic results. This report summarizes the demographic features of patients identified as biotinidase deficient from August of 2012 through August of 2013 and mutation analysis results for 20 cases in the southeast region of Turkey. Keywords: biotinidase deficiency; molecular analysis; newborn screening. DOI 10.1515/jpem-2014-0056 Received February 12, 2014; accepted October 22, 2014; previously published online November 25, 2014
*Corresponding author: Dr. Çiğdem Seher Kasapkara, Department of Pediatric Metabolism and Nutrition, Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey, E-mail: [email protected] Melek Akar and Heybet Tüzün: Department of Neonatology, Diyarbakır Children’s Hospital, Diyarbakır, Turkey Mehmet Nuri Özbek and Rıza Taner Baran: Department of Pediatric Endocrinology, Diyarbakır Children’s Hospital, Diyarbakır, Turkey Bedri Aldudak: Department of Cardiology, Diyarbakır Children’s Hospital, Diyarbakır, Turkey Tijen Tanyalçın: Department of Biochemistry, İzmir, Turkey
Introduction Biotin, an essential water-soluble B vitamin that cannot be endogenously synthesized in mammals and that is obtained by means of dietary sources, is the coenzyme for carboxylases in humans. The holocarboxylases are degraded proteolytically to biocytin, which is then cleaved by biotinidase releasing biotin for reutilization, thereby completing the biotin cycle. Biotinidase deficiency (BD) is inherited as an autosomal recessive trait (1, 2). Children with BD cannot cleave biocytin and, therefore, cannot recycle biotin. Untreated individuals become secondarily biotin deficient, which in turn results in decreased activities of the biotindependent carboxylases and the subsequent accumulation of toxic metabolites causing clinical symptoms (3). BD is characterized by neurological and cutaneous manifestations and metabolic abnormalities. Neurological symptoms of BD commonly include myoclonic seizures, ataxia, hypotonia, hearing loss, optic atrophy, and developmental delay. Non-neurological manifestations include alopecia, skin rash, and fungal infection due to reduced cellular immunity (4). Individuals with A, c.557G > A, c.1330G > C, c1368A > C, c1489C > T, and c1595C > T mutations in exon 4 in individuals with BD. We identified c. 470G > A (R157H) homozygous mutation in two patients with partial BD. The majority of the mutations detected in our study population comprised c. 470G > A (R157H) homozygous mutation in exon 4. A singlebase substitution, c. 470G > A (R157H), was observed in 10 patients (eight homozygous and two compound heterozygous). Two of the other mutations detected in more than one patient, c. 235C > T (p.R79C) and c. 1595C > T(p.T532M), were relatively common among patients with BD (Table 1).
Table 1 Biotinidase activity and mutation analysis results for 20 cases of BTD. Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Sex M M F F M F M M F M F F F M M M F M M F
Biotinidase activity, eu
Allele 1
Allele 2
0 10 14 14 0 0 6 11 28 18 0 22 8 15 0 0 29 0 1 24
c.235C > T c.235C > T c.1368A > C c.470G > A c.1595C > T c.1595C > T c. 470G > A c.1595C > T c.470 G > A c.470G > A c.557G > A c.470G > A c.1595C > T c.470G > A c.235C > T c.1330G > C c.470G > A c.235C > T c.470G > A c.470G > A
c.235C > T c.470G > A c.1368A > C c.470G > A c.1595C > T c.1595C > T c. 470G > A c.1595C > T c.470G > > A c.470G > A c.557G > A c.470G > A c.1595C > T c.1489C > T c.235C > T c.1330G > C c.470G > A c.235C > T c.470G > A c.470G > A
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Kasapkara et al.: Mutations in BTD gene causing biotinidase deficiency 423
Discussion Common symptoms of profound BD are presented during the first days of neonatal life and seldom during the first year. All the detected cases were asymptomatic except three of those and supplemented with biotin. Neonatal screening for BD is conducted in our country but not conducted properly because of parents’ noncompliance in the southeast part of Turkey. Therefore, the patients were rather old at the time of diagnosis. Individuals with untreated BD usually develop seizures, hypotonia, skin rash, alopecia, vision problems, hearing loss, and developmental delay with ketolactic acidosis and organic aciduria. Biotinidase enzyme catalyzes the release of biotin from breakdown products of carboxylases and, therefore, plays a crucial role in biotin recycling. Mutations in the BTD gene impair the recycling of biotin and lead to a substantial urinary loss of biotin in forms of biotinylated peptides (10–13). Sensorineural hearing loss in BD occurs in as many as 76% of individuals with symptoms. Hearing loss, visual abnormalities, and developmental delay are usually not reversible with administration of pharmacological doses of biotin (5–20 mg/day) (1). Therefore, it is important that BD is diagnosed early so that biotin therapy can be initiated before permanent neurological damage occurs (14, 15). Many countries including our country screen for this disorder at birth because early treatment with pharmacological doses of biotin can prevent the disorder from becoming symptomatic in children. We are now reporting mutations that cause BD. Newborn screening has enabled identification of children with profound and partial BD (16–18). However, in some cases, enzymatic activity does not adequately differentiate partial deficiency from heterozygosity for profound deficiency; therefore, mutation analysis is necessary to confirm the diagnosis (19). Because of the high rate of consanguinity in the southeastern part of Turkey, all children were the products of consanguineous mating, and all of the children were homozygous or compound heterozygous for specific mutations (c.235C > T in exon 2 and c.470G > A, c.557G > A, c.1330G > C, c1368A > C, c1489C > T, and c1595C > T mutations in exon 4) known to cause profound BD. This disorder remains one of the most preventable causes of mental retardation, vision problems, and hearing loss if diagnosed and treated with biotin before symptoms develop. Identifying the full spectrum of mutations that cause BD will undoubtedly be useful in determining the functional domains of the enzyme. Second-tier mutation analysis also provides valuable support to the enzymatic analysis and should be considered as a supplement to the biochemical data by those performing newborn screening
for BD. Newborn screening allows early presymptomatic treatment that can prevent neurological impairment (20– 22). In conclusion, we determined the mutation spectrum causing partial and profound BD in patients from the southeastern part of Turkey.
References 1. Sivri HS, Genç GA, Tokatli A, Dursun A, Coşkun T, et al. Hearing loss in biotinidase deficiency: genotype-phenotype correlation. J Pediatr 2007;150:439–42. Erratum in: J Pediatr 2007;151:222. 2. Milánkovics I, Kámory E, Csókay B, Fodor F, Somogyi C, et al. Mutations causing biotinidase deficiency in children ascertained by newborn screening in Western Hungary. Mol Genet Metab 2007;90:345–8. 3. Neto EC, Schulte J, Rubim R, Lewis E, DeMari J, et al. Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations. Braz J Med Biol Res 2004;37:295–9. 4. Dobrowolski SF, Angeletti J, Banas RA, Naylor EW. Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency. Mol Genet Metab 2003;78:100–7. 5. Wolf B, Jensen K, Hüner G, Demirkol M, Baykal T, et al. Seventeen novel mutations that cause profound biotinidase deficiency. Mol Genet Metab 2002;77:108–11. 6. Wolf B. Children with profound biotinidase deficiency should be treated with biotin regardless of their residual enzyme activity or genotype. Eur J Pediatr 2002;161:167–8; author reply 169. 7. Pettit DA, Amador PS, Wolf B. The quantitation of biotinidase activity in dried blood spots using microtiter transfer plates: identification of biotinidase-deficient and heterozygous individuals. Anal Biochem 1989;179:371–4. 8. Hymes J, Stanley CM, Wolf B. Mutations in BTD causing biotinidase deficiency. Hum Mutat 2001;18:375–81. 9. Blanton SH, Pandya A, Landa BL, Javaheri R, Xia X, et al. Fine mapping of the human biotinidase gene and haplotype analysis of five common mutations. Hum Hered 2000;50:102–11. 10. Pomponio RJ, Hymes J, Reynolds TR, Meyers GA, Fleischhauer K, et al. Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. Pediatr Res 1997;42:840–8. 11. Pomponio RJ, Reynolds TR, Mandel H, Admoni O, Melone PD, et al. Profound biotinidase deficiency caused by a point mutation that creates a downstream cryptic 3′ splice acceptor site within an exon of the human biotinidase gene. Hum Mol Genet 1997;6:739–45. 12. Pomponio RJ, Narasimhan V, Reynolds TR, Buck GA, Povirk LF, et al. Deletion/insertion mutation that causes biotinidase deficiency may result from the formation of a quasipalindromic structure. Hum Mol Genet 1996;5:1657–61. 13. Procter M, Wolf B, Crockett DK, Mao R. The Biotinidase Gene Variants Registry: a paradigm public database. G3: Genes | Genomes | Genetics 2013;3. Published online at April 2013. doi:pii: g3.113.005835v1. 10.1534/g3.113.005835. 14. Iqbal F, Item CB, Vilaseca MA, Jalan A, Mühl A, et al. The identification of novel mutations in the biotinidase gene using denatur-
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424 Kasapkara et al.: Mutations in BTD gene causing biotinidase deficiency ing high pressure liquid chromatography (dHPLC). Mol Genet Metab 2010;100:42–5. 15. Chedrawi AK, Ali A, Al Hassnan ZN, Faiyaz-Ul-Haque M, Wolf B. Profound biotinidase deficiency in a child with predominantly spinal cord disease. J Child Neurol 2008;23:1043–8. 16. Thodi G, Schulpis KH, Molou E, Georgiou V, Loukas YL, et al. High incidence of partial biotinidase deficiency cases in newborns of Greek origin. Gene 2013;524:361–2. 17. Tiar A, Mekki A, Nagara M, Rhouma FB, Messaoud O, et al. Biotinidase deficiency: novel mutations in Algerian patients. Gene. 2014;536(1):193–6. doi:pii: S0378-1119(13)00185-6. 10.1016/j. gene.2013.02.011.
18. Afroze B, Wasay M. Biotinidase deficiency in Pakistani children; what needs to be known and done. J Pak Med Assoc 2012;62:312–3. 19. Cowan TM, Kazerouni NN, Dharajiya N, Lorey F, Roberson M, et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab 2012;106:485–7. 20. Zempleni J, Kuroishi T. Biotin. Adv Nutr 2012;3:213–4. 21. Hayati AA, Wan-Hitam WH, Cheong MT, Yunus R, Shatriah I. Optic neuritis in a child with biotinidase deficiency: case report and literature review. Clin Ophthalmol 2012;6:389–95. 22. Küry S, Ramaekers V, Bézieau S, Wolf B. Clinical utility gene card for: biotinidase deficiency. Eur J Hum Genet 2012;20. doi: 10.1038/ejhg.2012.28.
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