Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta

Abstract

We report a sibling-pair and a 4-year old child from two families with an atypical presentation in Osteogenesis imperfecta (OI). In the sib-pair, the older sibling initially came to medical attention due to a fracture history (Patient 1) and she was shown to have a COL1A2 mutation. In addition, she also had developmental delay, facial dysmorphism, and a history of frequent infections which led to a search for an alternate diagnosis. ArrayCGH revealed a 4.3 Mb duplication on chromosome 19q13.42q13.43, which was confirmed by FISH analysis. On further familial analysis, the younger sibling who had no previous fracture history was also found to have the COL1A2 mutation and tested positive for the 19q13.42q13.43 duplication (Patient 2). The 19q13 duplication appears to be the cause of intellectual disability in these siblings but given that this is a chromosomal duplication, it is still possible that there is an as yet unidentified cause that may account for the combined phenotype in this family. Patient 3 was a 4-year old child presenting with a femoral fracture, blue sclerae, developmental delay, and joint hypermobility. Genetic analyses confirmed a COL1A2 mutation but also revealed an 8.8 Mb deletion of 11q24.2q25, confirmed by G-band chromosome analysis. We discuss the differing phenotypes in patients presenting with atypical OI and stress the need to consider ancillary investigations in individuals presenting with heterogeneous phenotypic symptoms, not entirely attributable to OI.

Three Offspring with Cri-du-Chat Syndrome from Phenotypically Normal Parents

“…Terminal 19q13.3 duplications have been reported to be associated with neuromotor retardation, speech delay, epilepsy, short stature, abnormal ears, and short neck [Bhat et al, 2000;Resta et al, 2013;Carvalheira et al, 2014]. Two siblings who had a 4.3-Mb duplication in 19q13.42q13.43 (similar to our patients) with learning difficulties, short stature, dysmorphic facial features including hypertelorism, low set ears, and prominent chin, have been described, and it is suggested that these patients have clinical features similar to 19q terminal duplication reported previously [Balasubramanian et al, 2016]. Although some dysmorphic features (hypertelorism, lowset ears) overlap between 5p deletion and 19q duplication, our patients did not have other features of 19q duplication like prominent chin.…”

Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen

“…(99) Moreover, common PLS3 variants have been associated with osteoporosis in postmenopausal women. (86,102) In subjects with PLS3-related EOOP, basic parameters of calcium homeostasis are normal and bone turnover markers are either normal or slightly reduced, (84,87,94,103) as compared with age-matched mutation-negative controls. However, PLS3 mutation-positive subjects had elevated DKK1 concentrations, suggesting that PLS3 impairment might also alter WNT signaling in bone.…”

Autism and heritable bone fragility: A true association?

“…They may have extreme short stature or developmental delay. In these cases, it may be that the patient has an atypical diagnosis of a type I collagenopathy ( Balasubramanian et al, 2016 ). Some patients with bone fragility display autistic traits which are not in keeping with their clinical diagnosis as children with OI are reported to have normal intelligence; this would be classified as ‘atypical bone fragility’.…”