Due to considerable phenotypic variability, Sillence et al.8,9 developed a classification of OI subtypes based on clinical features and disease severity (Table 1): OI type I, mild, common, with blue sclera; OI type II, perinatal lethal form; OI type III, severe and progressively deforming, with normal sclera; and OI type IV, moderate severity with normal sclera. The classification of Sillence has been repeatedly revised when new causative genes for OI are identified.

The molecular genetic classification of OI has shown to be very heterogeneous, with different patterns of inheritance and wide variability of clinical severity.10

Glorieux et al.11 described an autosomal dominant form of OI, similar to OI Sillence type IV, but with distinct clinical, histological, and molecular characteristics. No mutations were found in COL1A1 and COL1A2 and, therefore, it was called OI type V (OMIM #610967) by the authors. Approximately 65% of affected individuals develop hyperplastic callus after fractures or surgical interventions, considered a pathognomonic characteristic.12 Only in 2012 were IFITM5 mutations identified in patients with type V OI, the gene encoding interferon-induced transmembrane protein 5, by sequencing of the entire exome.12–14 The encoded protein has a role in early mineralization, but its mechanism remains unknown.10

In 2006, a CRTAP gene mutation was identified as the first genetic cause of lethal recessive OI.15 Since then, new mutations in genes that cause recessive OI have been identified by exome sequencing, such as FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP, BMP1, and TMEM38B. Each of these genes received an OI type number in the OMIM database, following the sequence numbers of the Sillence classification.

OI type VI (OMIM #613982) is an autosomal recessive form of the disease that can be caused by a homozygous mutation in the gene SERPINF1 in chromosome 17p13.3, causing a mineralization defect.14 According to the classification of Sillence et al., the phenotype is compatible with type IV or type III.16,17

OI type VII (MIM #610682) is a lethal autosomal recessive form of OI, caused by a mutation in CRTAP gene in homozygosity or compound heterozygosity in chromosome 3p22. It accounts for 2% to 3% of cases of lethal OI.15

Cabral et al.18 described a form of autosomal recessive OI, called OI type VIII (OMIM #610915), which is characterized by white sclera, severe growth impairment, very poor skeletal mineralization, and bulbous metaphyses. This form is caused by mutations in the gene encoding leprecan (LEPRE1) in chromosome 1p34.2, associated with severe or lethal OI.

OI type IX (OMIM #259440) is an autosomal recessive form of OI corresponding to clinically severe types II/III of the Sillence classification.19 There are no reports of dentinogenesis imperfecta. It can be caused by a homozygous mutation in the PPIB gene in chromosome 15q22.31.

OI type X (OMIM #613848) is an autosomal recessive form of the disease that can be caused by a homozygous mutation in the gene SERPINH1 in chromosome 11q13.5. It is characterized by bone deformities and multiple fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclera. SERPINH1 encodes a collagen-binding protein that acts as a chaperone in the endoplasmic reticulum and thus, individuals with mutations in this gene have cells that do not produce overmodified type I collagen.20

OI type XI (OMIM #610968) is an autosomal recessive form of the disease caused by a homozygous mutation in the FKBP10 gene in chromosome 17q21, also related to a chaperone defect.1 Patients with type OI type XI have severe progressive deformation and may have joint contractures. Patients do not have dentinogenesis imperfecta.21–23

OI type XII (OMIM #613849) is an autosomal recessive form, which can be caused by mutation in the SP7 gene in chromosome 12q13.13. It is clinically characterized by recurrent fractures, mild bone deformities, generalized osteoporosis, delayed eruption of teeth, absence of dentinogenesis imperfecta, normal hearing, and white sclera.24

OI type XIII (OMIM #614856) was described as caused by a homozygous mutation in the gene BMP1 in chromosome 8p21.25,26

Shaheen et al.27 described OI type XIV (OMIM # 615066), an autosomal recessive form characterized by varying degrees of severity with multiple fractures and osteopenia, with normal dentition, sclera, and hearing. Fractures occur prenatally or at approximately 6 years of age. It is caused by a homozygous mutation in the gene TMEM38B in chromosome 9q31.

OI type XV (OMIM #615220) has been designated based on the identification of mutations in WNT1.28–30 Keupp et al.30 reported that WNT1 hypofunctional alleles result in phenotypes with low bone mass in humans. They verified that mutations in the recessive inherited gene lead to phenotypes of varying severity, ranging from mild to progressively deforming, which can occasionally lead to early infant death. They also detected families that had early osteoporosis with the autosomal dominant pattern of inheritance, with a heterozygous mutation in WNT1.

The recessive forms of OI with moderate to lethal phenotypes are caused by defects in genes whose products interact with collagen type I. Most recessive cases have null mutations in genes encoding proteins involved in prolyl 3-hydroxylation of collagen (CRTAP, LEPRE1, and PPIB), or in those responsible for the correct helical folding (FKBP10 and SERPINH1). Types VII, VIII, and IX are caused by defects in 3-hydroxylation.1 The genotype-phenotype correlation in recessive forms has been suggested.31

In 2013, PLS3 mutations were identified in families with osteoporosis and fractures manifesting in childhood, with an X-linked pattern of inheritance.32

Table 2 summarizes the classification based on the involved genes.

In 2010, van Dijk et al.33 proposed a revised classification of OI, mentioning the causative gene and the corresponding clinical picture only for types I to VI. Types VII and VIII were excluded, as those types were added by genetic criteria, although their clinical and radiological findings were indistinguishable from those in types II to IV. The proposed classification leaves room for new genes discovered as the cause of OI until the full extent of heterogeneity is known.34

Due to the high genetic complexity of the molecular basis of OI and the extensive phenotypic variability resulting from individual loci described in recent years, it seemed impossible to maintain correlations between Sillence types and their molecular basis. But the proliferation of OI types to reflect each gene separately, supported by some, has become more confusing than useful in clinical practice. For these reasons, in 2009 the Nosology Group of the International Society of Skeletal Dysplasias recommended maintaining the classification of Sillence as the prototypical and universally accepted form to classify the degree of OI severity, and freeing it from direct molecular reference.35 Thus, as shown in Table 3, OI was grouped into five clinical categories, and the several genes that can cause OI were listed separately. In the present study, the genes IFITM5, SERPINF1, BMP1, WNT1, TMEM38B, and PLS3 were added to the original table, as they were discovered after its publication.