ReuseUnless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. Disclosures: All authors state that they have no conflicts of interest. Takedown Supplemental data not included with this paper (see separate files)2 AbstractContext:Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI; OMIM 611236) by dysregulating intracellular calcium flux. Objectives:Clinical and bone material phenotype description and osteoblast differentiation studies. Design and Setting:Natural history study in paediatric research centres.Patients:Eight patients with type XIV OI. Main Outcome Measures:Clinical examinations included; bone mineral density, radiographs, echocardiography and muscle biopsy. Bone biopsy samples (n=3) were analysed for histomorphometry and bone mineral density distribution by quantitative backscattered electron microscopy and Raman microspectroscopy. Cellular differentiation studies were performed on proband osteoblasts and normal murine osteoclasts. Results:The clinical phenotype of type XIV OI ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband L1-L4 bone density Z-score was reduced (median -3.3 [range -4.77 to +0.1; n=7]), and increased by +1.7 (1.17 to 3.0; n=3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone mineralization density is normal/slightly increased. We demonstrate a complex osteoblast differentiation defect with decreased 3 expression of early markers and increased late, mineralisation-related markers.Predominance of TRIC-B over TRIC-A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover.Conclusions: OI type XIV has a bone histology, mineralization and osteoblast differentiation pattern that is distinct from type I OI. Probands are responsive to bisphosphonates but show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities.4

IntroductionFoetal akinesia deformation sequence syndrome (FADS) is a genetically heterogeneous disorder characterised by the combination of foetal akinesia and developmental defects which may include pterygia (joint webbing). Traditionally multiple pterygium syndrome (MPS) has been divided into two forms: prenatally lethal (LMPS) and non-lethal Escobar type (EVMPS) types. Interestingly, FADS, LMPS and EVMPS may be allelic e.g. each of these phenotypes may result from mutations in the foetal acetylcholine receptor gamma subunit gene (CHRNG). Many cases of FADS and MPS do not have a mutation in a known FADS/MPS gene and we undertook molecular genetic studies to identify novel causes of these phenotypes.ResultsAfter mapping a novel locus for FADS/LMPS to chromosome 19, we identified a homozygous null mutation in the RYR1 gene in a consanguineous kindred with recurrent LMPS pregnancies. Resequencing of RYR1 in a cohort of 66 unrelated probands with FADS/LMPS/EVMPS (36 with FADS/LMPS and 30 with EVMPS) revealed two additional homozygous mutations (in frame deletions). The overall frequency of RYR1 mutations in probands with FADS/LMPS was 8.3%.ConclusionsOur findings report, for the first time, a homozygous RYR1 null mutation and expand the range of RYR1-related phenotypes to include early lethal FADS/LMPS. We suggest that RYR1 mutation analysis should be performed in cases of severe FADS/LMPS even in the absence of specific histopathological indicators of RYR1-related disease.

Introduction: Foetal akinesia deformation sequence syndrome (FADS) is a genetically heterogeneous disorder characterised by the combination of foetal akinesia and developmental defects which may include pterygia (joint webbing). Traditionally multiple pterygium syndrome (MPS) has been divided into two forms: prenatally lethal (LMPS) and non-lethal Escobar type (EVMPS) types. Interestingly, FADS, LMPS and EVMPS may be allelic e.g. each of these phenotypes may result from mutations in the foetal acetylcholine receptor gamma subunit gene (CHRNG). Many cases of FADS and MPS do not have a mutation in a known FADS/MPS gene and we undertook molecular genetic studies to identify novel causes of these phenotypes. Results: After mapping a novel locus for FADS/LMPS to chromosome 19, we identified a homozygous null mutation in the RYR1 gene in a consanguineous kindred with recurrent LMPS pregnancies. Resequencing of RYR1 in a cohort of 66 unrelated probands with FADS/LMPS/EVMPS (36 with FADS/LMPS and 30 with EVMPS) revealed two additional homozygous mutations (in frame deletions). The overall frequency of RYR1 mutations in probands with FADS/LMPS was 8.3%. Conclusions: Our findings report, for the first time, a homozygous RYR1 null mutation and expand the range of RYR1-related phenotypes to include early lethal FADS/LMPS. We suggest that RYR1 mutation analysis should be performed in cases of severe FADS/LMPS even in the absence of specific histopathological indicators of RYR1-related disease.

Multiple pterygium syndrome (MPS) disorders are a phenotypically and genetically heterogeneous group of conditions characterized by multiple joint contractures (arthrogryposis), pterygia (joint webbing) and other developmental defects. MPS is most frequently inherited in an autosomal recessive fashion but X-linked and autosomal dominant forms also occur. Advances in genomic technologies have identified many genetic causes of MPS-related disorders and genetic diagnosis requires large targeted next generation sequencing gene panels or genome-wide sequencing approaches. Using the Illumina TruSightOne clinical exome assay, we identified a recurrent heterozygous missense substitution in TPM2 (encoding beta tropomyosin) in three unrelated individuals.This was confirmed to have arisen as a de novo event in the two patients with parental samples. TPM2 mutations have previously been described in association with a variety of dominantly inherited neuromuscular phenotypes including nemaline myopathy, congenital fibre-type disproportion, distal arthrogryposis and trismus pseudocamptodactyly, and in a patient with autosomal recessive Escobar syndrome and a nemaline myopathy.The three cases reported here had overlapping but variable features. Our findings expand the range of TMP2-related phenotypes and indicate that de novo TMP2 mutations should be considered in isolated cases of MPS-related conditions. K E Y W O R D S arthrogryposis, beta tropomyosin, camptodactyly, distal contractures, multiple pterygium syndrome, TPM2, trismus

BackgroundThere is a substantial rise in the incidence of cancer in Saudi Arabia. Life style models and lack of awareness are the prime suspect in this substantial increase. Therefore, the objective of the present study was to assess the relationship between lifestyle and cancer in a population-based Survey in Northern Saudi Arabia.MethodologyThis cross-sectional study was conducted in North Saudi Arabia (Hail Region). Data was collected as a part of a community based cancer's awareness movement that covered an area inhibited with approximately 500,000 individuals.ResultsIn this study, about 2558/3227 (79.3%) and 641/794 (80.7%) believed that tobacco smoking and smokeless are not a risk of cancer development. In this study large section (87.2%) of the study population believe that exposure to diverse occupational or non-occupational chemicals has no role in cancer development. Furthermore, around 59% of the study subjects in the current study believed that repeated exposure to insecticidal chemicals doesn't influence the risk of cancer.ConclusionThe present study point to the urgent need for awareness educational programs and preventive measures towards may lifestyle factors that can increase or decrease the overall risk of cancer among Saudi population.