Autosomal recessive osteogenesis imperfecta (OI) accounts for 10% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed.

1.
Alanay Y, Avaygan H, Camacho N, Utine GE, Boduroglu K, et al: Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 86:551-559 (2010).
2.
Asharani PV, Keupp K, Semler O, Wang W, Li Y, et al: Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet 90:661-674 (2012).
3.
Basel D, Steiner RD: Osteogenesis imperfecta: recent findings shed new light on this once well-understood condition. Genet Med 11:375-385 (2009).
4.
Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, et al: Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 88:362-371 (2011).
5.
Caparrós-Martin JA, Valencia M, Pulido V, Martinez-Glez V, Rueda-Arenas I, et al: Clinical and molecular analysis in families with autosomal recessive osteogenesis imperfecta identifies mutations in five genes and suggests genotype-phenotype correlations. Am J Med Genet A 161A:1354-1369 (2013).
6.
Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ, et al: A single recurrent mutation in the 5′-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet 91:343-348 (2012).
7.
Cho SY, Ki CS, Sohn YB, Kim SJ, Maeng SH, Jin DK: Osteogenesis imperfecta type VI with severe bony deformities caused by novel compound heterozygous mutations in SERPINF1. J Korean Med Sci 28:1107-1110 (2013).
8.
Fahiminiya S, Majewski J, Mort J, Moffatt P, Glorieux FH, Rauch F: Mutations in WNT1 are a cause of osteogenesis imperfecta. J Med Genet 50:345-348 (2013).
9.
Faqeih E, Shaheen R, Alkuraya FS: WNT1 mutation with recessive osteogenesis imperfecta and profound neurological phenotype. J Med Genet 50:491-492 (2013).
10.
Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R: Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 17:723-728 (2002).
11.
Homan EP, Rauch F, Grafe I, Lietman C, Doll JA, et al: Mutations in SERPINF1 cause osteogenesis imperfecta type VI. J Bone Miner Res 26:2798-2803 (2011).
12.
Hubbard TJ, Aken BL, Ballester B, Beal K, Bragin E, et al: Ensembl 2009. Nucleic Acids Res 37:D690-D697 (2009).
13.
Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, et al: Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 92:565-574 (2013).
14.
Laine CM, Joeng KS, Campeau PM, Kiviranta R, Tarkkonen K, et al: WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med 368:1809-1816 (2013).
15.
Lapunzina P, Aglan M, Temtamy S, Caparrós-Martin JA, Valencia M, et al: Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am J Hum Genet 87:110-114 (2010).
16.
Li H, Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754-1760 (2009).
17.
Marini C, Scheffer LE, Nabbout R, Mei D, Cox K, et al: SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis. Epilepsia 50:1670-1678 (2009).
18.
Pyott SM, Tran TT, Leistritz DF, Pepin MG, Mendelsohn NJ, et al: WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am J Hum Genet 92:590-597 (2013).
19.
Rauch F, Glorieux FH: Osteogenesis imperfecta. Lancet 363:1377-1385 (2004).
20.
Rauch F, Husseini A, Roughley P, Glorieux FH, Moffatt P: Lack of circulating pigment epithelium-derived factor is a marker of osteogenesis imperfecta type VI. J Clin Endocrin Metab 97:1-7 (2012).
21.
Rohrbach M, Giunta C: Recessive osteogenesis imperfecta: clinical, radiological and molecular findings. Am J Med Genet C Semin Med Genet 160C:175-189 (2012).
22.
Semler O, Garbes L, Keupp K, Swan D, Zimmermann K, et al: A mutation in the 5′-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet 91:349-357 (2012).
23.
Shaheen R, Alazami AM, Alshammari MJ, Fageih E, Alhashmi N, et al: Study of autosomal recessive osteogenesis imperfect in Arabia reveals a novel locus defined by TMEM38B mutation. J Med Genet 49:630-635 (2012).
24.
Sillence DO, Senn A, Danks DM: Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16:101-116 (1979).
25.
Tucker T, Nelson T, Sirrs S, Roughley P, Glorieux FH, et al: A co-occurrence of osteogenesis imperfecta type VI and cystinosis. Am J Med Genet A 158A:1422-1426 (2012).
26.
van Dijk FS, Cobben JM, Kariminejad A, Maugeri A, Nikkels PG, et al: Osteogenesis imperfecta: a review with clinical examples. Mol Syndromol 2:1-20 (2011).
27.
van Dijk FS, Byers PH, Dalgleish R, Malfait F, Maugeri A, et al: EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta. Eur J Hum Genet 20:11-19 (2012).
28.
Venturi G, Monti E, Dalle Carbonare L, Corradi M, Gandini A, et al: A novel splicing mutation in FKBP10 causing osteogenesis imperfecta with a possible mineralization defect. Bone 50:343-349 (2012a).
29.
Venturi G, Gandini A, Monti E, Dalle Carbonare L, Corradi M, et al: Lack of expression of SERPINF1, the gene coding for pigment epithelium-derived factor, causes progressively deforming osteogenesis imperfecta with normal type I collagen. J Bone Miner Res 27:723-728 (2012b).
30.
Volodarsky M, Markus B, Cohen I, Staretz-Chacham O, Flusser H, et al: A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Hum Mutat 34:582-586 (2013).
31.
Wilson C: Wnt-1 - a key player in the regulation of human bone mass? Nat Rev Endocrinol 9:377 (2013).
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