Osteogenesis imperfecta (OI) is an inherited heterogeneous rare skeletal disorder characterized by increased bone fragility and low bone mass. The disorder mostly segregates in an autosomal dominant manner. However, several rare autosomal recessive and X-linked forms, caused by mutations in 18 different genes, have also been described in the literature.

Here, we present five consanguineous families segregating OI in an autosomal recessive pattern. Affected individuals in the five families presented severe forms of skeletal deformities. It included frequent bone fractures with abnormal healing, short stature, facial dysmorphism, osteopenia, joint laxity, and severe scoliosis. In order to search for the causative variants, DNA of at least one affected individual in three families (A-C) were subjected to whole exome sequencing (WES). In two other families (D-E), linkage analysis using highly polymorphic microsatellite markers was followed by Sanger sequencing. Sequence analysis revealed two novels and three previously reported disease-causing variants. The two novel homozygous variants including [c.824G > A; p.(Cys275Tyr)] in the SP7 gene and [c.397C > T, p.(Gln133*)] in the SERPINF1 gene were identified in families A and B, respectively. The three previously reported homozygous variants including [c.497G > A; p.(Arg166His)] in the SPARC gene, (c.359-3C > G; intron 2) and [c.677C > T; p.(Ser226Leu)] in the WNT1 gene were identified in family C, D, and E.

In conclusion, our findings provided additional evidence of involvement of homozygous sequence variants in the SP7, SERPINF1, SPARC and WNT1 genes causing severe OI. It also highlights the importance of extensive genetic investigations to search for the culprit gene in each case of skeletal deformity.

成骨不全症（OI）是一种遗传性异质性罕见骨骼疾病，其特征是骨脆性增加和骨量低。该疾病主要以常染色体显性方式分离。然而，文献中也描述了由 18 个不同基因突变引起的几种罕见的常染色体隐性遗传和 X 连锁遗传形式。

在这里，我们提出了五个以常染色体隐性模式分离 OI 的近亲家族。五个家庭中受影响的人都出现了严重的骨骼畸形。包括频繁骨折且愈合异常、身材矮小、面部畸形、骨质减少、关节松弛和严重脊柱侧凸。为了寻找致病变异，对三个家族 (AC) 中至少一名受影响个体的 DNA 进行了全外显子组测序 (WES)。在另外两个家族 (DE) 中，使用高度多态性微卫星标记进行连锁分析，然后进行桑格测序。序列分析揭示了两种新的致病变异和三种先前报道的致病变异。这两个新的纯合变体包括[c.824G>A； SP7基因中的 p.(Cys275Tyr)] 和SERPINF1基因中的 [c.397C > T, p.(Gln133*)] 分别在家族 A 和 B 中被鉴定。先前报道的三个纯合变异包括[c.497G>A； SPARC基因中的 p.(Arg166His)]，（c.359-3C > G；内含子 2）和 [c.677C > T；在 C、D 和 E 家族中鉴定出WNT1基因中的 p.(Ser226Leu)]。

总之，我们的研究结果提供了SP7 、 SERPINF1 、 SPARC和WNT1基因中纯合序列变异参与导致严重 OI 的额外证据。它还强调了广泛的基因研究以寻找每个骨骼畸形病例的罪魁祸首基因的重要性。