Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias

Abstract

Skeletal dysplasias are a diverse group of rare Mendelian disorders with clinical and genetic heterogeneity. Here, we used targeted copy number variant (CNV) screening and identified intragenic exonic duplications, formed through Alu-Alu fusion events, in two individuals with skeletal dysplasia and negative exome sequencing results. First, we detected a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD) (MIM# 208500). Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Complementary zebrafish studies suggested that loss of full-length IFT81 protein but expression of a shorter form of IFT81 protein affects the phenotype while being compatible with life. Second, a de novo tandem duplication of exons 2 to 5 in MATN3 was identified in a girl with multiple epiphyseal dysplasia (MED) type 5 (MIM# 607078). Our data highlights the importance of detection and careful characterization of intragenic duplication CNVs, presenting them as a novel and very rare genetic mechanism in IFT81-related Jeune syndrome and MATN3-related MED.

From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability

“…As has been shown previously [29, 78, 89, 90], our data confirms the notion that structural variants are important contributors also to Mendelian diseases (12/156, 7.7%). The LAMA2 duplication identified in RD_P394 and RD_P395 may represent a founder mutation.…”

“…Taken together, the breakpoint junctions from both patients harboring insertional duplications revealed no evidence for DNA replication errors, which has been the proposed mechanism underlying the formation of duplications in several cases [68, 78, 79].…”

Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues

“…42 Additionally, a recent study has highlighted that missense mutations confined to exon 2 of MATN3 are not the only cause of EDM5 as a de novo tandem duplication of exons 2-5 in MATN3 was recently identified in a patient diagnosed with MED. 43 To date, the cell pathology of EDM5 has been well documented using a genetically relevant mouse model and a surrogate cell models. [44][45][46][47] Studies have shown that mutations in the vWFA domain of matrilin-3 cause misfolding and protein retention, similar to the disease mechanism resulting from mutations in COMP.…”

Expanding the phenotypic spectrum of IFT81: Associated ciliopathy syndrome

“…The novel and overlapping clinical features of the previously reported six cases, as well as our new case of IFT81 ‐associated ciliopathy syndrome are summarized in Figure 2 (Dharmat et al, 2017; Duran et al, 2016; Perrault et al, 2015; Pettersson et al, 2018). At present, there are no clinical features that are unifying in all reported cases.…”

“…However, our patient did not have any of the ectodermal features that one would commonly see in CED, such as sparse hair, dysplastic teeth or abnormal nails (Walczak‐Sztulpa et al, 2010). To date, three individuals reported in the literature with variants in IFT81 have also had dolichocephaly, with no reported ectodermal features (Duran et al, 2016; Pettersson et al, 2018), adding further evidence that IFT81 should be considered in suspected ciliopathy cases where dolichocephaly is a presenting feature.…”