Supplemental Table 1. Pathogenic or likely pathogenic variants found in the present study

Gene / cDNA Change / Amino Acid Change / N* / Impact / Novel# / PolyPhen2 / SIFT / PhyloP / ExAc / Comment
COL1A1 / c.1012G>A / p.Gly338Ser / 1 / Gly / No / 0.983 / 0 / 4.15 / 0.00005 (2 of 43590 alleles) / OIVD: Causes OI type I, III or IV
COL1A1 / c.1678G>T / p.Gly560Cys / 1 / Gly / No / 1 / 0 / 5.33 / 0 / OIVD: Causes OI type IV
COL1A1 / c.1876-1G>C / - / 1 / Splice / No / 5.51 / 0 / OIVD: Causes OI type IV
COL1A1 / c.1984-5del / - / 1 / Splice / No / - / 0 / OIVD: Causes OI type I
COL1A1 / c.2089C>T / p.Arg697* / 1 / HI / No / - / 0 / OIVD: Causes OI type I
COL1A1 / c.3421C>T / p.Arg1141* / 1 / HI / No / - / 0 / OIVD: Causes OI type I
COL1A2 / c.632G>T / p.Gly211Val / 1 / Gly / No / 1 / 0 / 5.85 / 0 / OIVD: Causes OI type I
COL1A2 / c.838G>A / p.Gly280Ser / 2 / Gly / No / 1 / 0 / 6.29 / 0.000008 (1 of 121402 alleles) / OIVD: Causes OI type I or IV
COL1A2 / c.1523G>C / p.Gly508Ala / 1 / Gly / Yes / 0.999 / 0 / 6.26 / 0
COL1A2 / c.1595G>A / p.Gly532Glu / 1 / Gly / No / 0.999 / 0 / 6.10 / 0 / OIVD: Causes OI type IV
COL1A2 / c.2369G>C / p.Gly790Ala / 1 / Gly / No / 0.998 / 0 / 6.07 / 0 / OIVD: Causes OI type I
LRP5 / c.2737dup / p.Cys913Leufs*73 / 1 / HI / No / 0 / Reported in [1, 2]
LRP5 / c.3107G>A / p.Arg1036Gln / 5 / Missense / No / 0.998 / 0.04 / 1.72 / 0.002 (302 of 121382 alleles) / Reported in [2, 3]
LRP5 / c.3446T>A / p.Leu1149Gln / 1 / Missense / No / 1 / 0 / 4.42 / 0.0003 (41 of 120176 alleles) / Reported in [2]
LRP5 / c.3762_3762delA / p.Glu1255Serfs*18 / 1 / HI / Yes / - / - / - / 0
BMP1 / c.2107G>C + c.*241T>C / - / 1 / Splice / No / - / - / 0 / Reported in [4]
BMP1 / c.*241T>C + c.*241T>C / - / 3 / 3’UTR / No / - / - / 0 / Reported in [4]
PLS3 / c.994_995del / p.Asp332* / 1 / Stop / No / - / - / 0 / Reported in [5]
PLS3 / c.1433T>C / p.Leu478Pro / 1 / Missense / No / 0.991 / 0 / 4.39 / 0 / Reported in [5]

* Number of individuals with this mutation; # mutation not listed in the OI variant database (OIVD;

Abbreviations: Gly: Glycine substitution in the triple-helical domain of collagen type I; HI: variant leading to haploinsufficiency; hom: homozygous variant; Splice: Mutation affecting splicing. Polyphen2, SIFT and PhyloP are the names of the software algorithms and databases that were used to characterize the observed variants.

Supplemental Table 2. Variants of unknown significance found in the present study

Gene / cDNA Change / Amino Acid Change / N* / Impact / Novel# / PolyPhen2 / SIFT / PhyloP / ExAc / Comment
LRP5 / c.266A>G
/ p.Gln89Arg / 5 / Missense / No / 0.001 / 0.01 / 2.25 / 0.017
(2109 of 120984 alleles) / 86 individuals in ExAc database are homozygous for this variant
LRP5 / c.3280G>A / p.Glu1094Lys / 1 / Missense / Yes / 0.99 / 0 / 5.81 / 0
LRP5 / c.3404G>A / p.Arg1135His / 1 / Missense / Yes / 1.0 / 0 / 4.19 / 0.00006
(7 of 115994 alleles)
LRP5 / c.3641C>T / p.Ala1214Val / 1 / Missense / Yes / 0.001 / 0.28 / 1.13 / 0.00002
(2 of 121380 alleles)
LRP5 / c.4132G>C / p.Asp1378His / 1 / Missense / Yes / 0.54 / 0.274 / 3.82 / 0

* Number of individuals with this mutation; # mutation not listed in the OI variant database (

Abbreviations: Gly: Glycine substitution in the triple-helical domain of collagen type I; HI: variant leading to haploinsufficiency; Splice: Mutation affecting splicing. Polyphen2, SIFT and PhyloP are the names of the software algorithms and databases that were used to characterize the observed variants.

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Supplemental References

1.Fahiminiya S, Majewski J, Roughley P, Roschger P, Klaushofer K, Rauch F (2013) Whole-exome sequencing reveals a heterozygous LRP5 mutation in a 6-year-old boy with vertebral compression fractures and low trabecular bone density. Bone 57:41-46

2.Korvala J, Juppner H, Makitie O, et al. (2012) Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med Genet 13:26

3.Saarinen A, Saukkonen T, Kivela T, Lahtinen U, Laine C, Somer M, Toiviainen-Salo S, Cole WG, Lehesjoki AE, Makitie O (2010) Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin Endocrinol (Oxf) 72:481-488

4.Fahiminiya S, Al-Jallad H, Majewski J, Palomo T, Moffatt P, Roschger P, Klaushofer K, Glorieux FH, Rauch F (2015) A polyadenylation site variant causes transcript-specific BMP1 deficiency and frequent fractures in children. Hum Mol Genet 24:516-524

5.Fahiminiya S, Majewski J, Al-Jallad H, Moffatt P, Mort J, Glorieux FH, Roschger P, Klaushofer K, Rauch F (2014) Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics. J Bone Miner Res 29:1805-1814

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