Skeletal dysplasias are often well characterized, and only a minority of the cases remain unsolved after a thorough analysis of pathogenic variants in over 400 genes that are presently known to cause monogenic skeletal diseases. Here, we describe an 11-year-old Finnish girl, born to unrelated healthy parents, who had severe short stature and a phenotype similar to odontochondrodysplasia (ODCD), a monogenic skeletal dysplasia caused by biallelic TRIP11 variants. The family had previously lost a fetus due to severe skeletal dysplasia. Exome sequencing and bioinformatic analysis revealed an oligogenic inheritance of a heterozygous nonsense mutation in TRIP11 and four likely pathogenic missense variants in FKBP10, TBX5, NEK1, and NBAS in the index patient. Interestingly, all these genes except TBX5 are known to cause skeletal dysplasia in an autosomal recessive manner. In contrast, the fetus was found homozygous for the TRIP11 mutation, and achondrogenesis type IA diagnosis was, thus, molecularly confirmed, indicating two different skeletal dysplasia forms in the family. To the best of our knowledge, this is the first report of an oligogenic inheritance model of a skeletal dysplasia in a Finnish family. Our findings may have implications for genetic counseling and for understanding the yet unsolved cases of rare skeletal dysplasias.

Odontochondrodysplasia (ODCD, OMIM #184260) is a rare, non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene (TRIP11; OMIM *604505). The TRIP11 gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus. Mutations in TRIP11 also cause achondrogenesis type 1A (ACG1A). Null mutations of TRIP11 lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as ODCD with a novel compound heterozygous mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling achondroplasia and hypochondroplasia.

More than two decades since the first clinical and radiological description of odontochondroplasia (ODCD) was reported, biallelic loss of function variants in the Thyroid hormone receptor interactor 11 gene (TRIP11) were identified, the same gene implicated in the lethal disorder achondrogenesis (ACG1A). Here we report the clinical and radiological follow-up of four ODCD patients, including two siblings and an adult who interestingly has the mildest form observed to date. Four TRIP11 variants were detected, two previously unreported. Subsequently, we review the clinical and radiological findings of the 14 reported ODCD patients. The majority of ODCD patients are compound heterozygotes for TRIP11 variants, 12/14 have a null allele and a splice variant whilst one is homozygous for an in-frame splicing variant, with the splice variants resulting in residual GMAP activity and hypothesized to explain why they have ODCD and not ACG1A. However, adult patient 4 has two potentially null alleles and it remains unknown why she has very mild clinical features. The c.586C>T; p.(Gln196*) variant, previously shown by mRNA studies to result in p.Val105_Gln196del, is the most frequent variant, present in seven individuals from four families, three from different regions of the world, suggesting that it may be a variant hotspot. Another variant, c.2993_2994del; p.(Lys998Serfs*5), has been observed in two individuals with a possible common ancestor. In summary, although there are clinical and radiological characteristics common to all individuals, we demonstrate that the clinical spectrum of TRIP11-associated dysplasias is even more diverse than previously described and that common genetic variants may exist.

The thyroid hormone receptor interactor 11 (TRIP11) gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), a protein essential for the operation of the Golgi apparatus. It is known that null mutations in TRIP11 disrupt Golgi function and cause a lethal skeletal dysplasia known as achondrogenesis type 1A (ACG1A), however recently, hypomorphic mutations in that gene have been linked to odontochondrodysplasia (ODCD), a nonlethal skeletal dysplasia characterized by skeletal changes in the spine and in the metaphyseal regions, associated with dentinogenesis imperfecta. Here we present two patients reflecting the phenotypic spectrum related to different TRIP11 variants. The first is a female child with ODCD, for whom a homozygous in-frame splicing mutation in intron 9 of TRIP11 was identified. The mutation appears to lead to the expression of an alternative TRIP11 transcript, that may explain the less severe radiological alterations in ODCD. The second is a fetus with classical form of ACG1A, associated with typical molecular findings (frameshift) in exon 11 of TRIP11, both novel mutations. The two patients reported here represent the TRIP11 spectrum of skeletal dysplasia ranging from mild to lethal phenotypes, thereby enabling one to suggest a genotype-phenotype correlation in these diseases.