Erratum: Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations
Yamaguti PM, Neves FDAR, Hotton D, et al. Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations. J Med Genet 2017;54:26–37. One of the author names is spelled incorrectly. ‘Pascal Houiller’ should be ‘Pascal Houillier’. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Tags: Miscellaneous Source Type: research

Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment
Conclusion Migalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Authors: Mauer, M., Sokolovskiy, A., Barth, J. A., Castelli, J. P., Williams, H. N., Benjamin, E. R., Najafian, B. Tags: Open access Therapeutics Source Type: research

Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy
Conclusion These results indicated that C3-mediated complement activation might be altered in Fabry disease and ERT might promote its stabilisation. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Authors: Heo, S. H., Kang, E., Kim, Y.-M., Go, H., Kim, K. Y., Jung, J. Y., Kang, M., Kim, G.-H., Kim, J.-M., Choi, I.-H., Choi, J.-H., Jung, S.-C., Desnick, R. J., Yoo, H.-W., Lee, B. H. Tags: Open access Biochemical genetics Source Type: research

Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density
Conclusion Our results suggest that the iDCM-related SCN5A variants in the DI-S4 could predispose electrical disorders by reducing peak sodium current density. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Authors: Shen, C., Xu, L., Han, S., Dong, Z., Zhao, X., Wang, S., Qian, S., Li, B., Ma, X., Wang, P., Zhu, H., Zou, Y., Fan, Z., Ge, J., Sun, A. Tags: Genotype-phenotype correlations Source Type: research

Mutations in MYO1H cause a recessive form of central hypoventilation with autonomic dysfunction
Conclusions Our results identify MYO1H as an important gene in CO2 sensitivity and respiratory control and as the cause of a rare recessive form of congenital central hypoventilation. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Authors: Spielmann, M., Hernandez-Miranda, L. R., Ceccherini, I., Weese-Mayer, D. E., Kragesteen, B. K., Harabula, I., Krawitz, P., Birchmeier, C., Leonard, N., Mundlos, S. Tags: New disease loci Source Type: research

Incremental cost-effectiveness of algorithm-driven genetic testing versus no testing for Maturity Onset Diabetes of the Young (MODY) in Singapore
This study tests whether a novel algorithm-driven genetic testing strategy for MODY is incrementally cost-effective relative to the setting of no testing. Methods A decision tree was constructed to estimate the costs and effectiveness of the algorithm-driven MODY testing strategy and a strategy of no genetic testing over a 30-year time horizon from a payer’s perspective. The algorithm uses glutamic acid decarboxylase (GAD) antibody testing (negative antibodies), age of onset of diabetes (
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Authors: Nguyen, H. V., Finkelstein, E. A., Mital, S., Gardner, D. S.-L. Tags: Diagnostics Source Type: research

Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry
This study assesses breast cancer risk in a large prospectively followed LS cohort. Methods Pedigrees of 325 unrelated families with LS within the Familial Gastrointestinal Cancer Registry in Canada were examined for breast cancer diagnoses. Standardised incidence ratios (SIR) and lifetime cumulative incidence calculations were used to compare the incidence of breast cancer in mutation carriers with the general population. Results Forty-one mutation carriers diagnosed with breast cancer belonging to 34 unrelated families were identified. Mean age at diagnosis was 54 years. The mutation distribution among the LS patients ...
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Authors: Goldberg, M., Bell, K., Aronson, M., Semotiuk, K., Pond, G., Gallinger, S., Zbuk, K. Tags: Cancer genetics Source Type: research

Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks
Conclusions Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Authors: Decker, B., Allen, J., Luccarini, C., Pooley, K. A., Shah, M., Bolla, M. K., Wang, Q., Ahmed, S., Baynes, C., Conroy, D. M., Brown, J., Luben, R., Ostrander, E. A., Pharoah, P. D., Dunning, A. M., Easton, D. F. Tags: Evidence based practice, Open access Cancer genetics Source Type: research

DNA repair-related functional assays for the classification of BRCA1 and BRCA2 variants: a critical review and needs assessment
Mutation of BRCA1 and BRCA2 is the most common cause of inherited breast and ovarian cancer. Genetic screens to detect carriers of variants can aid in cancer prevention by identifying individuals with a greater cancer risk and can potentially be used to predict the responsiveness of tumours to therapy. Frequently, classification cannot be performed based on traditional approaches such as segregation analyses, including for many missense variants, which are therefore referred to as variants of uncertain significance (VUS). Functional assays provide an important alternative for classification of BRCA1 and BRCA2 VUS. As revie...
Source: Journal of Medical Genetics - October 23, 2017 Category: Genetics & Stem Cells Authors: Toland, A. E., Andreassen, P. R. Tags: Editor's choice Cancer genetics Source Type: research

Bi-allelic variants in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts
Conclusion Homozygous or compound heterozygous mutations in COL3A1 are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelic COL3A1 mutations emphasises the critical role of the type III collagen–GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Vandervore, L., Stouffs, K., Tanyalcin, I., Vanderhasselt, T., Roelens, F., Holder-Espinasse, M., Jorgensen, A., Pepin, M. G., Petit, F., Khau Van Kien, P., Bahi-Buisson, N., Lissens, W., Gheldof, A., Byers, P. H., Jansen, A. C. Tags: Original Article Source Type: research

GPRASP2, a novel causative gene mutated in an X-linked recessive syndromic hearing loss
Conclusions This study presented a novel X-linked SHL combined with unique and unrecognised clinical features, and a missense variation of GPRASP2 was first identified to be implicated in X-linked SHL. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Xing, G., Yao, J., Liu, C., Wei, Q., Qian, X., Wu, L., Lu, Y., Cao, X. Tags: Open access New loci Source Type: research

Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation
Conclusions Overall, heterozygous pathogenic variants in ribosomal genes were identified in 44 of the 61 families (72%). De novo pathogenic variants were observed in 57% of patients with DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Mirabello, L., Khincha, P. P., Ellis, S. R., Giri, N., Brodie, S., Chandrasekharappa, S. C., Donovan, F. X., Zhou, W., Hicks, B. D., Boland, J. F., Yeager, M., Jones, K., Zhu, B., Wang, M., Alter, B. P., Savage, S. A. Tags: New loci Source Type: research

LMNA-associated partial lipodystrophy: anticipation of metabolic complications
Conclusions This study is a rare example of anticipation unrelated to a trinucleotide expansion. Discovery of this early occurrence of metabolic complications in young generations underlines the utility of presymptomatic genetic diagnosis, with careful metabolic screening and preventive lifestyle in all at-risk individuals. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Jeru, I., Vatier, C., Vantyghem, M.-C., Lascols, O., Vigouroux, C. Tags: Phenotypes Source Type: research

Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration
Conclusions These findings substantiate the causality of frequent missense variants and their phenotypic outcomes as a significant contribution to ABCA4 disease, particularly the late-onset phenotype, and its clinical variation. They also suggest a significant revision of diagnostic screening and assessment of ABCA4 variation in aetiology of retinal diseases. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Zernant, J., Lee, W., Collison, F. T., Fishman, G. A., Sergeev, Y. V., Schuerch, K., Sparrow, J. R., Tsang, S. H., Allikmets, R. Tags: Genotype-phenotype correlations Source Type: research

Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome
Conclusion Recently, NUP107 was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other NUP107-reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for NUP107 in the regulation of brain growth and a GAMOS-like presentation. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Rosti, R. O., Sotak, B. N., Bielas, S. L., Bhat, G., Silhavy, J. L., Aslanger, A. D., Altunoglu, U., Bilge, I., Tasdemir, M., Yzaguirrem, A. D., Musaev, D., Infante, S., Thuong, W., Marin-Valencia, I., Nelson, S. F., Kayserili, H., Gleeson, J. G. Tags: Short Report Source Type: research

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1
Conclusions Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Kapplinger, J. D., Erickson, A., Asuri, S., Tester, D. J., McIntosh, S., Kerr, C. R., Morrison, J., Tang, A., Sanatani, S., Arbour, L., Ackerman, M. J. Tags: Open access Genotype-phenotype correlations Source Type: research

Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus
Background A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 – 4.5 Mb) located at 8p23. Initially implicated genes included FAM167A-BLK and XKR6, of which BLK received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported. Objective and methods In this case –control study, we further investigated the ‘extended’ 8p23 locus (~ 4 Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion a...
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Demirci, F. Y., Wang, X., Morris, D. L., Feingold, E., Bernatsky, S., Pineau, C., Clarke, A., Ramsey-Goldman, R., Manzi, S., Vyse, T. J., Ilyas Kamboh, M. Tags: Complex traits Source Type: research

Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes
Oral–facial–digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent d...
Source: Journal of Medical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Bruel, A.-L., Franco, B., Duffourd, Y., Thevenon, J., Jego, L., Lopez, E., Deleuze, J.-F., Doummar, D., Giles, R. H., Johnson, C. A., Huynen, M. A., Chevrier, V., Burglen, L., Morleo, M., Desguerres, I., Pierquin, G., Doray, B., Gilbert-Dussardier, B., Re Tags: Editor's choice Developmental defects Source Type: research

Decreased telomere length in children with cartilage-hair hypoplasia
Background Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical a...
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Kostjukovits, S., Degerman, S., Pekkinen, M., Klemetti, P., Landfors, M., Roos, G., Taskinen, M., Mäkitie, O. Tags: Telomere biology Source Type: research

Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy
Conclusions We identified and replicated a genetic association at 22q12.2 with tonsillectomy. Further functional investigation is required to illuminate whether the molecular mechanisms underlying the genetic association involve general lymphoid hyper-reaction throughout the mucosa-associated lymphoid tissue system. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Feenstra, B., Bager, P., Liu, X., Hjalgrim, H., Nohr, E. A., Hougaard, D. M., Geller, F., Melbye, M. Tags: Genome-wide studies Source Type: research

Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy
Conclusions Biallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Gerber, S., Ding, M. G., Gerard, X., Zwicker, K., Zanlonghi, X., Rio, M., Serre, V., Hanein, S., Munnich, A., Rotig, A., Bianchi, L., Amati-Bonneau, P., Elpeleg, O., Kaplan, J., Brandt, U., Rozet, J.-M. Tags: Genotype-phenotype correlations Source Type: research

Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B
Conclusions The pathogenic basis for one synonymous mutation (Val107Val) in the F9 gene associated with haemophilia B was determined. A mechanistic understanding of this synonymous variant yields potential for guiding and developing future therapeutic treatments. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Simhadri, V. L., Hamasaki-Katagiri, N., Lin, B. C., Hunt, R., Jha, S., Tseng, S. C., Wu, A., Bentley, A. A., Zichel, R., Lu, Q., Zhu, L., Freedberg, D. I., Monroe, D. M., Sauna, Z. E., Peters, R., Komar, A. A., Kimchi-Sarfaty, C. Tags: Genotype-phenotype correlations Source Type: research

ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism
Conclusions Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in the cytosol and thereby facilitates transport into the peroxisome and subsequent β-oxidation. Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired VLCFA metabolism, leading to retinal dystrophy and white matter disease. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Ferdinandusse, S., Falkenberg, K. D., Koster, J., Mooyer, P. A., Jones, R., van Roermund, C. W. T., Pizzino, A., Schrader, M., Wanders, R. J. A., Vanderver, A., Waterham, H. R. Tags: Genetic screening / counselling Functional genomics Source Type: research

No correlation between mtDNA amount and methylation levels at the CpG island of POLG exon 2 in wild-type and mutant human differentiated cells
Conclusions This study suggests that, at variance with mouse and un/de-differentiated human cells, differentiated human cells control mtDNA levels irrespective of POLG methylation. The factors which actually control the mtDNA levels in such cell types remain to be identified. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Steffann, J., Pouliet, A., Adjal, H., Bole, C., Fourrage, C., Martinovic, J., Rolland-Galmiche, L., Rotig, A., Tores, F., Munnich, A., Bonnefont, J.-P. Tags: Epigenetics Source Type: research

A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium
Conclusions Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Noordam, R., Sitlani, C. M., Avery, C. L., Stewart, J. D., Gogarten, S. M., Wiggins, K. L., Trompet, S., Warren, H. R., Sun, F., Evans, D. S., Li, X., Li, J., Smith, A. V., Bis, J. C., Brody, J. A., Busch, E. L., Caulfield, M. J., Chen, Y.-D. I., Cummings Tags: Editor's choice Complex traits Source Type: research

Gastric cancer: somatic genetics as a guide to therapy
Gastric cancer is the leading cause of cancer-related mortality across the world, with poor prognosis and a median overall survival of ≤12 months for advanced stage gastric cancer. Environmental, genetic and other predisposing factors contribute to the development of gastric cancer and a predominant factor was found to be infection of Helicobacter pylori. Advances in understanding the deranged signalling pathways that are critical for normal cellular homeostasis helped in the development of novel drugs that target specific proteins and pathways to curtail the growth of gastric cancer. Genetic studies revealed sever...
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Zhang, X.-y., Zhang, P.-y. Tags: Immunology (including allergy), Reproductive medicine, Pancreatic cancer, Screening (oncology), Epidemiology, Drugs: endocrine system Review Source Type: research

Outcome of 24 years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance
Background Individuals with hereditary non-polyposis colorectal cancer (HNPCC) have a high risk of colorectal cancer (CRC). The benefits of colonic surveillance in Lynch syndrome and Amsterdam-positive (familial CRC type X familial colorectal cancer type X (FCCTX)) families are clear; only the interval between colonoscopies is debated. The potential benefits for families not fulfilling the Amsterdam criteria are uncertain. The aim of this study was to compare the outcome of colonic surveillance in different hereditary subgroups and to evaluate the surveillance programmes. Methods A prospective, observational study on the ...
Source: Journal of Medical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Lindberg, L. J., Ladelund, S., Frederiksen, B. L., Smith-Hansen, L., Bernstein, I. Tags: Screening Source Type: research

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study
Conclusions Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations. Trial registration number: NCT00925301; Pre-results. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Hughes, D. A., Nicholls, K., Shankar, S. P., Sunder-Plassmann, G., Koeller, D., Nedd, K., Vockley, G., Hamazaki, T., Lachmann, R., Ohashi, T., Olivotto, I., Sakai, N., Deegan, P., Dimmock, D., Eyskens, F., Germain, D. P., Goker-Alpan, O., Hachulla, E., Jo Tags: Open access, Metabolic disorders Therapeutics Source Type: research

Congenital valvular defects associated with deleterious mutations in the PLD1 gene
Conclusions The findings support a role for PLD1 in normal heart valvulogenesis. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Ta-Shma, A., Zhang, K., Salimova, E., Zernecke, A., Sieiro-Mosti, D., Stegner, D., Furtado, M., Shaag, A., Perles, Z., Nieswandt, B., Rein, A. J. J. T., Rosenthal, N., Neiman, A. M., Elpeleg, O. Tags: Immunology (including allergy), Congenital heart disease, Reproductive medicine, Valvar diseases, Clinical diagnostic tests New loci Source Type: research

AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
Conclusions Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome. Functional analysis confirms mutant-specific protein dysfunction. We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Andreoletti, G., Seaby, E. G., Dewing, J. M., O'Kelly, I., Lachlan, K., Gilbert, R. D., Ennis, S. Tags: Open access, Genetic screening / counselling, Renal medicine, Calcium and bone, Metabolic disorders New loci Source Type: research

Diagnostic value of exome and whole genome sequencing in craniosynostosis
Conclusions This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Miller, K. A., Twigg, S. R. F., McGowan, S. J., Phipps, J. M., Fenwick, A. L., Johnson, D., Wall, S. A., Noons, P., Rees, K. E. M., Tidey, E. A., Craft, J., Taylor, J., Taylor, J. C., Goos, J. A. C., Swagemakers, S. M. A., Mathijssen, I. M. J., van der Sp Tags: Open access, Molecular genetics, Calcium and bone Developmental defects Source Type: research

Impact of subsidies on cancer genetic testing uptake in Singapore
We report findings of a pilot study that evaluates how different subsidy schemes impact genetic testing uptake and total cost of cancer management. Methods We included all patients who attended the Cancer Genetics Service at the National Cancer Centre Singapore (January 2014–May 2016). Two subsidy schemes, the blanket scheme (100% subsidy to all eligible patients), and the varied scheme (patients received 50%–100% subsidy dependent on financial status) were compared. We estimated total spending on cancer management from government's perspective using a decision model. Results 445 patients were included. ...
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Li, S.-T., Yuen, J., Zhou, K., Binte Ishak, N. D., Chen, Y., Met-Domestici, M., Chan, S. H., Tan, Y. P., Allen, J. C., Lim, S. T., Soo, K. C., Ngeow, J. Tags: Cancer genetics Source Type: research

Common cancers share familial susceptibility: implications for cancer genetics and counselling
Conclusions A strong family history of cancer, regardless of tumour type, increases cancer risk of family members and calls for mechanistic explanations. Our data provide tools for counselling of patients with cancer with both low and high familiar risks. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Yu, H., Frank, C., Sundquist, J., Hemminki, A., Hemminki, K. Tags: Prostate cancer, Urological cancer Original article Source Type: research

Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency
Conclusions MHSA can be caused by sequence variants in GSTZ1. Such individuals have thus far remained asymptomatic despite receiving no specific treatment. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Yang, H., Al-Hertani, W., Cyr, D., Laframboise, R., Parizeault, G., Wang, S. P., Rossignol, F., Berthier, M.-T., Giguere, Y., Waters, P. J., Mitchell, G. A., the Quebec NTBC Study Group, Alvarez, Brunel-Guitton, Buhas, Dubois, Gosselin, Halac, Maranda, Mi Tags: Liver disease, Genetic screening / counselling, Epidemiology, Metabolic disorders Genotype-phenotype correlations Source Type: research

A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family
Conclusions These findings thus contribute to a growing list of ID disorders caused by CRBN mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype–phenotype correlations between CRBN mutations and the aetiology of ARNS-ID. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Sheereen, A., Alaamery, M., Bawazeer, S., Al Yafee, Y., Massadeh, S., Eyaid, W. Tags: Open access Genotype-phenotype correlations Source Type: research

Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles
Conclusions The effect of complex alleles partially depends on the mutation in trans. Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Terlizzi, V., Castaldo, G., Salvatore, D., Lucarelli, M., Raia, V., Angioni, A., Carnovale, V., Cirilli, N., Casciaro, R., Colombo, C., Di Lullo, A. M., Elce, A., Iacotucci, P., Comegna, M., Scorza, M., Lucidi, V., Perfetti, A., Cimino, R., Quattrucci, S. Tags: Pancreas and biliary tract, Editor's choice, Genetic screening / counselling, Molecular genetics, Cystic fibrosis Genotype-phenotype correlations Source Type: research

The UCL low-density lipoprotein receptor gene variant database: pathogenicity update
Conclusions This study updates the LDLR variant database and identifies a number of reported VUS where additional family and in vitro studies will be required to confirm or refute their pathogenicity. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 22, 2017 Category: Genetics & Stem Cells Authors: Leigh, S., Futema, M., Whittall, R., Taylor-Beadling, A., Williams, M., den Dunnen, J. T., Humphries, S. E. Tags: Open access, Lipid disorders, Metabolic disorders Original article Source Type: research

A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome
Conclusions We hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Bar, D. Z., Arlt, M. F., Brazier, J. F., Norris, W. E., Campbell, S. E., Chines, P., Larrieu, D., Jackson, S. P., Collins, F. S., Glover, T. W., Gordon, L. B. Tags: Open access, Molecular genetics, Metabolic disorders Somatic mosaicism Source Type: research

A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy
Conclusion This mutation has complex functional effects on GABAA receptors, including reduction of cell surface expression and attenuation of channel function, which would significantly perturb GABAergic inhibition in the brain. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Ishii, A., Kang, J.-Q., Schornak, C. C., Hernandez, C. C., Shen, W., Watkins, J. C., Macdonald, R. L., Hirose, S. Tags: Open access, Genetic screening / counselling, Epilepsy and seizures Source Type: research

Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability
Conclusions PIGC joins the list of genes in which mutations result in defective biosynthesis of GPI anchoring, manifesting by global developmental delay and seizure disorder. The lack of specific biomarker dictates exome sequencing as the diagnostic procedure of choice in similar patients. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Edvardson, S., Murakami, Y., Nguyen, T. T. M., Shahrour, M., St-Denis, A., Shaag, A., Damseh, N., Le Deist, F., Bryceson, Y., Abu-Libdeh, B., Campeau, P. M., Kinoshita, T., Elpeleg, O. Tags: Genetic screening / counselling, Immunology (including allergy), Epilepsy and seizures New loci Source Type: research

CEP78 is mutated in a distinct type of Usher syndrome
Conclusions Our results provide evidence that CEP78 is a novel disease-causing gene for Usher syndrome, demonstrating an additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Fu, Q., Xu, M., Chen, X., Sheng, X., Yuan, Z., Liu, Y., Li, H., Sun, Z., Li, H., Yang, L., Wang, K., Zhang, F., Li, Y., Zhao, C., Sui, R., Chen, R. Tags: Eye Diseases, Hereditary eye disease, Genetic screening / counselling New loci Source Type: research

Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix
Conclusions At least some cases of PSEK result from loss-of-function mutations in KRT83. Heterozygous missense substitutions in KRT83 have been implicated in autosomal dominant monilethrix, a rare hair disorder. Our findings indicate that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the KRT83 gene. Together, these findings indicate that different types of mutations in KRT83 can result in quite different skin and hair phenotypes. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Shah, K., Ansar, M., Mughal, Z.-u.-N., Khan, F. S., Ahmad, W., Ferrara, T. M., Spritz, R. A. Tags: Genotype-phenotype correlations Source Type: research

A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima
Conclusions The identified novel TRAPPC11 mutation represents an expansion of the myopathy phenotype described before and is characterised particularly by achalasia, alacrima, neurological and muscular phenotypes. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Koehler, K., Milev, M. P., Prematilake, K., Reschke, F., Kutzner, S., Jühlen, R., Landgraf, D., Utine, E., Hazan, F., Diniz, G., Schuelke, M., Huebner, A., Sacher, M. Tags: Genetic screening / counselling, Molecular genetics, Immunology (including allergy), Muscle disease, Neuromuscular disease, Calcium and bone Genome-wide studies Source Type: research

Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone
Conclusions VEGF is an important angiogenic signal required for tissue expansion. We show that VEGFA variation giving allele-specific response to transcription factors with overlapping binding sites associate closely with circulating TSH levels. Because CHOP is induced by several types of intracellular stress, this indicates that cellular stress could be involved in the normal or pathophysiological response of the thyroid to TSH. Trial registration number NCT00289237, NCT00316667; Results. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Ahluwalia, T. S., Troelsen, J. T., Balslev-Harder, M., Bork-Jensen, J., Thuesen, B. H., Cerqueira, C., Linneberg, A., Grarup, N., Pedersen, O., Hansen, T., Dalgaard, L. T. Tags: Immunology (including allergy), Reproductive medicine, Drugs: endocrine system Functional genomics Source Type: research

Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene
Conclusions We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution in ERF. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Balasubramanian, M., Lord, H., Levesque, S., Guturu, H., Thuriot, F., Sillon, G., Wenger, A. M., Sureka, D. L., Lester, T., Johnson, D. S., Bowen, J., Calhoun, A. R., Viskochil, D. H., DDD Study, Bejerano, G., Bernstein, J. A., Chitayat, D. Tags: Calcium and bone Developmental defects Source Type: research

The importance of dynamic re-analysis in diagnostic whole exome sequencing
Exome sequencing technologies are constantly evolving, with exome capture systems covering more coding bases, and the continual development of improved alignment and variant-calling programmes. At the same time, new genes are frequently being implicated in Mendelian genetic disease. In many cases, therefore, the generation of extra coverage, updating of alignment and variant calling tools and regular inspection for novel gene-disease associations emerging in the literature will yield a diagnosis that was not found in the initial analysis. The rates of diagnosis with exome sequencing range from 25% to 40%.1 The diagnosis ra...
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Need, A. C., Shashi, V., Schoch, K., Petrovski, S., Goldstein, D. B. Tags: Commentary Source Type: research

Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum
Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS a...
Source: Journal of Medical Genetics - February 17, 2017 Category: Genetics & Stem Cells Authors: Ji, A.-L., Zhang, X., Chen, W.-W., Huang, W.-J. Tags: Editor's choice Review Source Type: research

The performance of deleteriousness prediction scores for rare non-protein-changing single nucleotide variants in human genes
In recent years, whole genome sequencing has increasingly been used as a replacement of whole exome sequencing for identifying causal variants of human diseases. In response to this trend, several ‘genome-level’ deleteriousness prediction scores have been proposed to implement the scores designed specifically for missense or splicing variants. The aim of this study was to investigate the prediction accuracy of those genome-level scores for rare non-protein-changing single nucleotide variants (npcSNVs) in and near human genes. We compared 15 genome-level deleteriousness prediction scores and eight conservation s...
Source: Journal of Medical Genetics - January 19, 2017 Category: Genetics & Stem Cells Authors: Liu, X., Li, C., Boerwinkle, E. Tags: Functional genomics Source Type: research

Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma
Conclusions This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18 years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - January 19, 2017 Category: Genetics & Stem Cells Authors: Burnichon, N., Mazzella, J.-M., Drui, D., Amar, L., Bertherat, J., Coupier, I., Delemer, B., Guilhem, I., Herman, P., Kerlan, V., Tabarin, A., Wion, N., Lahlou-Laforet, K., Favier, J., Gimenez-Roqueplo, A.-P. Tags: Genetic screening / counselling, Molecular genetics, Screening (oncology), Epidemiology Cancer genetics Source Type: research

The cerebellum and embodied semantics: evidence from a case of genetic ataxia due to STUB1 mutations
Abundant research on lexicosemantic processing indicates that damage to movement-related regions (the motor and premotor cortices, Broca's area and the basal ganglia1) distinctively impairs processing of action verbs, that is, verbs denoting bodily motion. Moreover, such deficits could be hereditary,2 suggesting an association with genetic factors. We, thus, hypothesised that genetically based deterioration of other motor regions could involve similar impairments. In particular, through a combination of structural and functional MRI (fMRI) with genetic and behavioural analysis, this case study indicates that distinctive ac...
Source: Journal of Medical Genetics - January 19, 2017 Category: Genetics & Stem Cells Authors: Garcia, A. M., Abrevaya, S., Kozono, G., Cordero, I. G., Cordoba, M., Kauffman, M. A., Pautassi, R., Munoz, E., Sedeno, L., Ibanez, A. Tags: Genetic screening / counselling, Parkinson's disease, Clinical diagnostic tests, Ethics Cognitive and behavioural genetics Source Type: research