Osteogenesis imperfecta in Brazilian patients

Trancozo, Maira; Moraes, Marcos V.D.; Silva, Dalila A.; Soares, Jéssica A.M.; Barbirato, Clara; Almeida, Márcio G.; Santos, Lígia R.; Rebouças, Maria R. G. O.; Akel, Akel N.; Sipolatti, Valentim; Nunes, Vanda R. R.; Errera, Flavia I. V.; Aguena, Meire; Passos-Bueno, Maria R.; Paula, Flavia de

doi:10.1590/1678-4685-GMB-2018-0043

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Human and Medical Genetics • Genet. Mol. Biol. 42 (2) • Apr-Jun 2019 • https://doi.org/10.1590/1678-4685-GMB-2018-0043 copy

Osteogenesis imperfecta in Brazilian patients

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Osteogenesis Imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and fracture. Mutations in 20 distinct genes can cause OI, and therefore, the genetic diagnosis of OI is frequently difficult to obtain because of the great number of genes that can be related with this disease. Studies that report the most frequently mutated genes in OI patients can help to improve molecular strategies for diagnosis of the disease. In order to characterize the mutation profile of OI in Brazilian patients, we analyzed 30 unrelated patients through SSCP screening, NGS gene panel, and/or Sanger sequencing for the 11 most frequently mutated genes in the database of mutations, including COL1A1, COL1A2, P3H1, CRTAP, PPIB, SERPINH1, SERPINF1, FKBP10, SP7, WNT1 and IFITM5. Disease-causing variants were identified in COL1A1, COL1A2, FKBP10, P3H1, and IFITM5. A total of 28 distinct mutations were identified, including seven novel changes. Our data show that the analysis of these five genes is able to detect at least 95% of causative mutations in OI disorder from Brazilian population. However, it has to be taken into considerations that distinct populations can have different frequencies of disease-causing variants. Hence, it is important to replicate this study in other groups.

Keywords:
NGS gene panel; COL1A1/COL1A2 genes; FKBP10 gene; P3H1 gene; IFITM5 gene

Patient	Gene	Exon/Intron	Mutation (cDNA)	Mutation (protein)	Mutation type	Zygosity	OI phenotype	Familial	Novel	Mutation detection technique	OI type
P.1	COL1A1	Exon 8	c.608G > T	p.Gly203Val	Missense	Heterozygous	severe	No	No	NGS	III
P.2	COL1A1	Exon 13	c.887G > T	p.Gly296Val	Missense	Heterozygous	mild	Yes	Yes	NGS	I
P.3	COL1A1	Intron 16	c.1056+1G > A	Splice Site	Splicing	Heterozygous	moderate	No	No	SSCP	IV
P.4	COL1A1	Exon 17	c.1138G > T	p.Gly380Cys	Missense	Heterozygous	mild	Yes	No	SSCP	I
P.5	COL1A1	Exon 18	c.1165G > T	p.Gly389Cys	Missense	Heterozygous	moderate	No	No	NGS	IV
P.6	COL1A1	Intron 27	c.1875+1G > C	Splice Site	Splicing	Heterozygous	severe	No	No	SSCP	III
P.7	COL1A1	Exon 32	c.2165G > C	p.Gly722Ala	Missense	Heterozygous	mild	No	Yes	NGS	I
P.8	COL1A1	Exon 37	c.2523delT	p.(Gly842Alafs*266)	Frameshift	Heterozygous	mild	Yes	No	NGS	I
P.9	COL1A1	Intron 37	c.2559+1G > A	Splice Site	Splicing	Heterozygous	mild	Yes	No	SSCP	I
P.10	COL1A1	Exon 40	c.2750delG	p.(Gly917Aspfs*191)	Frameshift	Heterozygous	severe	Yes	Yes	SSCP	III
P.11	COL1A1	Exon 44	c.3162delT	p.(Gly1055Alafs*53)	Frameshift	Heterozygous	mild	N/A	No	NGS	I
P.12	COL1A1	Exon 45	c.3235G > A	p.Gly1079Ser	Missense	Heterozygous	mild	Yes	No	SSCP	I
P.13	COL1A1	Exon 45	c.3235G > A	p.Gly1079Ser	Missense	Heterozygous	mild	Yes	No	NGS	I
P.14	COL1A1	Exon 45	c.3239delC	p.(Pro1080Leufs*28)	Frameshift	Heterozygous	severe	No	Yes	SSCP	III
P.15	COL1A2	Intron 14	c.693+2T > C	Splice Site	Splicing	Heterozygous	moderate	No	No	NGS	IV
P.16	COL1A2	Exon 16	c.739G > C	p.Gly247Arg	Missense	Heterozygous	moderate	No	No	SSCP	IV
P.17	COL1A2	Exon 34	c.2027G > A	p.Gly676Asp	Missense	Heterozygous	mild	No	No	NGS	I
P.18	COL1A2	Exon 38	c.2314G > A	p.Gly772Ser	Missense	Heterozygous	mild	No	No	NGS	I
P.19	COL1A2	Exon 38	c.2314G > A	p.Gly772Ser	Missense	Heterozygous	mild	Yes	No	NGS	I
P.20	COL1A2	Intron 40	c.2565+1G > A	Splice Site	Splicing	Heterozygous	moderate	No	No	NGS	IV
P.21	COL1A2	Exon 40	c.2458G > A	p.Gly820Ser	Missense	Heterozygous	severe	No	No	NGS	III
P.22	COL1A2	Exon 49	c.3278G > A	p.Gly1093Asp	Missense	Heterozygous	severe	No	No	NGS	III
P.23	COL1A2	Exon 49	c.3296G > C	p.Gly1099Ala	Missense	Heterozygous	severe	No	Yes	NGS	III
P.24	IFITM5	5`UTR	c.-14C > T	p.Met1ext-5	Start Codon	Heterozygous	severe	No	No	Sanger S	V
P.25	P3H1	Intron 5	c.1080+1G > T	Splice Site	Splicing	Homozygous	severe	No	No	SSCP	VIII
P.26	P3H1	Exon 14	c.2024G > T	p.Trp675Leu	Missense	Heterozygous	severe	Yes	No	SSCP/NGS	VIII
P.27	FKBP10	Exon 1	c.21dupC	p.Ser8Glnfs*67	Frameshift	Homozygous	moderate	No	No	NGS	XI
P.28	FKBP10	Exon 1	c.179A > C	p.Gln60Pro	Missense	Heterozygous	moderate	No	Yes	NGS	XI
		Intron 6	c.1063+2T > C	Splice Site	Splicing	Heterozygous
P.29	FKBP10	Exon 5	c.831dupC	p.Gly278Argfs*95	Frameshift	Homozygous	severe	No	No	SSCP	XI
P.30	-	-	-	-	-	-	mild	No	-	-	-

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[1] Send correspondence to Flavia de Paula. Laboratório de Genética Humana e Molecular, Departamento de Ciências Biológicas, Centro de Ciências Humanas e Naturais, Universidade Federal do Espírito Santo, Av. Fernando Ferrari, 514, 29.075-910 Vitória, ES, Brazil. E-mail: flapvit@yahoo.com.br