Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants

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Abstract

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.

Introduction

In 1991, Goldblatt et al. described a child with a unique spondylometaphyseal dysplasia (SMD) with mesomelic short stature, generalized joint laxity and dentinogenesis imperfecta (Goldblatt et al., 1991). In 1992, a sib pair born to non-consanguineous parents was reported to have a spondyloepimetaphyseal dysplasia (SEMD), with similar features (Bonaventure et al., 1992). Later, Maroteaux et al. (1996), described two unrelated males with growth retardation, ligamentous hyperextensibility, scoliosis, dentinogenesis imperfecta and irregular metaphyses on X-ray (Maroteaux et al., 1996). Six additional individuals, including a second sib pair (brother and sister), with clinical and radiographic findings that were sufficiently homogeneous to confirm the SMD as a distinct entity were reported and the name of odontochondrodysplasia (ODCD, MIM 184260) was proposed (Unger et al., 2008).

In 2019, more than two decades since the first clinical and radiological description was reported, biallelic loss of function variants in the Thyroid hormone receptor interactor 11 gene (TRIP11) were detected, the same gene implicated in the lethal disorder achondrogenesis (ACG1A, MIM 200600), a skeletal dysplasia characterized by short trunk, narrow chest, short extremities and cranio-facial malformations (Smits et al., 2010; Mortier et al., 2019; Wehrle et al., 2019). A total of 13 variants have been reported in 11 ODCD patients from eight unrelated families (Wehrle et al., 2019; Medina et al., 2020).

TRIP11 encodes the Golgi-associated microtubule-binding protein 210 (GMAP-210), a member of the Golgin protein family, as it contains a central coiled-coil domain and a GRAB (GRIP related ARF1 binding) domain (Infante et al., 1999; Ramos-Morales et al., 2001). Homozygous GMAP-210 mice with the p.Leu1668* nonsense variant showed that the lack of GMAP-210 results in errors in glycan processing and impaired specific extracellular matrix proteoglycan secretion by the Golgi apparatus (Smits et al., 2010; Bird et al., 2018; Wehrle et al., 2019).

Here, we report the detailed clinical and radiological follow up of four patients with ODCD including two siblings and an adult, and show that the clinical spectrum is even more diverse than previously described.

Section snippets

Clinical reports

We report the clinical and radiological description of four patients from three families, patients 1–3 from Argentina and patient 4 from Spain. Their growth has been evaluated according to the population where they come from. For the Argentinean patients, birth data, weights and heights were evaluated using the populational data from Lejarraga et al. (2009), head circumference (HC) (Nellhaus 1968), and sitting height/height SH/H) ratios (Pino et al., 2017). The growth curves for Spanish patient

Patient 1

Argentine girl born by Cesarean section at 38 weeks of gestation to healthy non-consanguineous parents (Fig. 1A). Birth weight was 3700 g (+1.07 SDS) but her length was not recorded. Both parents are of normal height with no skeletal anomalies.

At age 7.25 years, she had her first examination at our center. She presented with severe short stature (84.9 cm, −6.9 SDS, Supp Fig 1A) and weighed 14 kg (−2.94 SDS). She had dentinogenesis imperfecta (Fig. 1B), joint laxity, small and asymmetric trunk

Patient 2

Patient 2, the younger brother of patient 1, was born at term by Cesarean delivery, following an uneventful pregnancy. His birth weight was 3500 g (+0.4 SDS) but birth length was not recorded. He was delayed in walking (4y) but his intellectual development was normal.

At 5.5 years old, he was referred to our hospital with severe short stature 63.2 cm (−10.4 SDS, Supp Fig. 1C) and a weight of 10.1 kg (−3.89 SDS). He presented with relative macrocephaly, dentinogenesis imperfecta (Fig. 1C),

Patient 3

This Argentine girl was previously reported as patient 7 in Wehrle et al. (2019). She was born at term at 37 weeks gestation to healthy non-consanguineous parents, following an uneventful pregnancy except for the detection of short long bones on ultrasound. Her birth length was 43 cm (−3.5 SDS) and weight 2800 g (−0.9 SDS). She had a normal female karyotype, brain ultrasound examination, ophthalmologic evaluation and otoacoustic emissions.

She was referred to the Hospital Garrahan at the age of

Patient 4

Female patient, age 38, was referred from obstetrics for genetic evaluation due to recurrent (n = 3) miscarriages and skeletal abnormalities compatible with a skeletal dysplasia. She was born by vaginal delivery, from healthy non-consanguineous parents after a controlled pregnancy without incidences. Her birth weight was 3500 g. At age 3 she presented with progressive scoliosis requiring a brace at age 5.5 years. At age 7 years she was reported to have many dental caries. At age 13.5 years, she

Genetic studies

All participants provided informed consent for the performed studies and ethical approval was obtained from local ethical committees. Blood samples were extracted from the patients and their parents. Patients 1 and 2 were analysed using a custom designed Skeletal dysplasia Next generation sequencing (NGS) panel, SKELETALSEQ.V8 (n = 416 genes) as previously described (Vasques et al., 2018). Patient 4 underwent whole exome sequencing (WES) whilst the variants had already been reported for patient

Discussion

We report here the clinical, radiological and genetic features of four ODCD patients from three unrelated families. ODCD has been characterized with severe disproportionate short stature due to mesomelic shortening of the limbs, scoliosis, joint laxity, macrocephaly, brachydactyly and dentinogenesis imperfecta. Indeed, patients 1–3 fulfill these characteristics.

The clinical and radiological features of the two siblings (patients 1 and 2) are different. Although both presented with severe

Author statement

Mariana del Pino: Resources, Investigation, Visualization, Writing - Original draft. Mary José Sanchez-Soler: Resources, Investigation, Writing - review & editing. Manuel Parrón-Pajares: Investigation, Visualization, Writing – Original draft, Writing-review & editing. Miriam Aza-Carmona: Investigation, Writing – review & editing. Karen E. Heath: Conceptualization, Methodology, Investigation, Resources, Writing-review & editing, Visualization, Supervision, Project administration, Funding

Funding

This work was supported from a grant (SAF 2017-84646-R) from the Ministerio de Economia, Industria y Competividad (to K.E.H), and cofunded by the “Fondo Europeo de Desarrollo Regional” (FEDER).

Declaration of competing interest

The authors have not conflict of interest to disclose related to the content of this manuscript.

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