Genetic variants of TREML2 are associated with HLA-B27-positive ankylosing spondylitis.

Gene. 2018 May 17;:

Authors: Feng Y, Hong Y, Zhang X, Cao C, Yang X, Lai S, Fan C, Cheng F, Yan M, Li C, Huang W, Chen W, Zhu P, Zeng C

Abstract
Although ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the precise genetic mechanism underlying the disease remains elusive. Here, we investigate the disease-causing mutations in a large AS family with distinguished complexity, consisting of 23 patients covering four generations and exhibiting a mixed HLA-B27 (+) and (-) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (-) patient, and one healthy individual did not identify a mutation common to all of the patients, strongly suggesting the existence of genetic heterogeneity in this large pedigree. However, if only B27-positive patients were analyzed, the linkage analysis located a 22-Mb region harboring the HLA gene cluster in chromosome 6 (LOD = 4.2), and the subsequent exome analysis identified two non-synonymous mutations in the TREML2 and IP6K3 genes. These genes were resequenced among 370 sporadic AS patients and 487 healthy individuals. A significantly higher mutation frequency of TREML2 was observed in AS patients (1.51% versus 0.21%). The results obtained for the AS pedigree and sporadic patients suggest that mutation of TREML2 is a major factor leading to AS for HLA-B27 (+) members in this large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals.

PMID: 29778423 [PubMed - as supplied by publisher]

Comprehensive molecular diagnosis of Epstein-Barr virus-associated lymphoproliferative diseases using next-generation sequencing.

Int J Hematol. 2018 May 18;:

Authors: Ono S, Nakayama M, Kanegane H, Hoshino A, Shimodera S, Shibata H, Fujino H, Fujino T, Yunomae Y, Okano T, Yamashita M, Yasumi T, Izawa K, Takagi M, Imai K, Zhang K, Marsh R, Picard C, Latour S, Ohara O, Morio T

Abstract
Epstein-Barr virus (EBV) is associated with several life-threatening diseases, such as lymphoproliferative disease (LPD), particularly in immunocompromised hosts. Some categories of primary immunodeficiency diseases (PIDs) including X-linked lymphoproliferative syndrome (XLP), are characterized by susceptibility and vulnerability to EBV infection. The number of genetically defined PIDs is rapidly increasing, and clinical genetic testing plays an important role in establishing a definitive diagnosis. Whole-exome sequencing is performed for diagnosing rare genetic diseases, but is both expensive and time-consuming. Low-cost, high-throughput gene analysis systems are thus necessary. We developed a comprehensive molecular diagnostic method using a two-step tailed polymerase chain reaction (PCR) and a next-generation sequencing (NGS) platform to detect mutations in 23 candidate genes responsible for XLP or XLP-like diseases. Samples from 19 patients suspected of having EBV-associated LPD were used in this comprehensive molecular diagnosis. Causative gene mutations (involving PRF1 and SH2D1A) were detected in two of the 19 patients studied. This comprehensive diagnosis method effectively detected mutations in all coding exons of 23 genes with sufficient read numbers for each amplicon. This comprehensive molecular diagnostic method using PCR and NGS provides a rapid, accurate, low-cost diagnosis for patients with XLP or XLP-like diseases.

PMID: 29777376 [PubMed - as supplied by publisher]

The clinical implications of G1-G6 transcriptomic signature and 5-gene score in Korean patients with hepatocellular carcinoma.

BMC Cancer. 2018 May 18;18(1):571

Authors: Ahn SM, Haq F, Park I, Nault JC, Zucman-Rossi J, Yu E

Abstract
BACKGROUND: Efforts have been made to classify Hepatocellular Carcinoma (HCC) at surgically curable stages because molecular classification, which is prognostically informative, can accurately identify patients in need of additional early therapeutic interventions. Recently, HCC classification based French studies on the expression of 16 genes and 5 genes were proposed. In 16-gene classification, transcriptomic signatures (G1-G6) were used to classify HCC patients into clinical, genomic and pathway-specific subgroups. In 5-gene score classification, the good or poor prognosis of HCC patients was predicted. The patient's cohort in these studies was mainly from Caucasian and African populations. Here, we aimed to validate G1-G6 and 5-gene score signatures in 205 Korean HCC patients since genomic profiles of Korean patients are distinct from other regions.
METHODS: Integrated analyses using whole-exome sequencing, copy number variation and clinical data was performed against these two signatures to find statistical correlations. Kaplan-Meier, univariate and multivariate COX regression analysis were performed for Disease-Specific Survival (DSS) and Recurrence-Free Survival (RFS).
RESULTS: The G2 and G3 subgroups of transcriptomic signature were significantly associated with TP53 mutations while G5 and G6 subgroups were significantly associated with CTNNB1 mutations which is in concordance with original French studies. Similarly, the poor prognosis group of 5-gene score showed shorter DSS (p = 0.045) and early RFS (p = 0.023) as well as a significant association with microvascular invasion, tumor size (> 5 cm), elevated AFP levels, and RB1 mutations. However, the 5-gene score was not an independent prognostic factor for survival.
CONCLUSION: The G1-G6 and 5-gene signatures showed significant concordance between genetic profiles of Korean HCC patients and patients in original French studies. Thus, G1-G6 and 5-gene score signatures can be targeted as potential therapeutic biomarkers against HCC patients worldwide.

PMID: 29776391 [PubMed - in process]

Bethlem myopathy in a Portuguese patient - case report.

Acta Myol. 2017 Sep;36(3):178-181

Authors: Martins AI, Maarque C, Pinto-Basto J, Negrão L

Abstract
Mutations of the encoding genes of collagen VI (COL6A1, COL6A2 and COL6A3), are responsible for two classical phenotypes (with a wide range of severity), the Ullrich congenital muscular dystrophy (UCMD) and the Bethlem myopathy (BM). We present a male patient of 49 years old, with symptoms of muscle weakness beginning in childhood and of very slowly progression. At the age of 42, the neurological examination revealed proximal lower limb muscle weakness and contractures of fingers flexors muscles, positive Gowers manoeuvre and a waddling gait. Serum creatine kinase (CK) values were slightly elevated, electromyographic study revealed myopathic changes and muscle MRI of the lower limbs showed a specific pattern of muscle involvement, with peripheral fat infiltration in vastus lateralis and intermedius and anterocentral infiltration in rectus femoris. Respiratory and cardiac functions were unremarkable. Whole exome sequencing identified the homozygous mutation c.1970-9G>A in COL6A2 gene.

PMID: 29774307 [PubMed - in process]

Independent Tumor Origin in Two Cases of Synchronous Bilateral Clear Cell Renal Cell Carcinoma.

Sci Rep. 2016 07 07;6:29267

Authors: Ji Z, Zhao J, Zhao T, Han Y, Zhang Y, Ye H

Abstract
Bilateral renal cell carcinomas (RCCs) pose a challenge for clinical treatment and management. Most bilateral RCCs are sporadic, and do not show a hereditary pattern indicative of VHL syndrome or other inherited cancers. The origin and evolution of these sporadic bilateral RCCs remains elusive. We obtained normal and tumor samples from two male patients suffering from early stage synchronous bilateral clear cell RCC (ccRCC), and analyzed genomic DNA using whole exome sequencing and bisulfite pyrosequencing. We detected distinct 3p loss of heterozygosity (LOH) in both tumors in each patient. Two tumors within the same patient harbored distinct driver mutations and different CpG hypermethylation sites in the VHL promoter. Moreover, tumors exhibit independent evolutionary trajectories. Therefore, distinct 3p LOH, combined with contingent driver gene mutations and independent VHL hypermethylation, led to independent tumor origin and parallel evolution of bilateral ccRCC in these two patients. Our results indicate that tumors in these two cases were not due to common germline oncogenic mutations. They were results of multiple de novo mutations in each kidney, rather than primary ccRCC with contralateral renal metastasis. Therefore, histopathologic and genetic profiling from single tumor specimen may underestimate the mutational burden and somatic heterogeneity of bilateral ccRCCs.

PMID: 27383411 [PubMed - indexed for MEDLINE]

Visual impairment and progressive phthisis bulbi caused by recessive pathogenic variant in MARK3.

Hum Mol Genet. 2018 May 16;:

Authors: Ansar M, Chung H, Waryah YM, Makrythanasis P, Falconnet E, Rao AR, Guipponi M, Narsani AK, Fingerhut R, Santoni FA, Ranza E, Waryah AM, Bellen HJ, Antonarakis SE

Abstract
Developmental eye defects often severely reduce vision. Despite extensive efforts, for a substantial fraction of these cases the molecular causes are unknown. Recessive eye disorders are frequent in consanguineous populations and such large families with multiple affected individuals provide an opportunity to identify recessive causative genes. We studied a Pakistani consanguineous family with three affected individuals with congenital vision loss and progressive eye degeneration. The family was analyzed by exome sequencing of one affected individual and genotyping of all family members. We have identified a non-synonymous homozygous variant (NM_001128918.2:c.1708C>G:p.Arg570Gly) in the MARK3 gene as the likely cause of the phenotype. Given that MARK3 is highly conserved in flies (I: 55%; S: 67%) we knocked down the MARK3 homologue, par-1, in the eye during development. This leads to a significant reduction in eye size, a severe loss of photoreceptors and loss of vision based on electroretinogram (ERG) recordings. Expression of the par-1 p.Arg792Gly mutation (equivalent to the MARK3 variant found in patients) in developing fly eyes also induces loss of eye tissue and reduces the ERG signals. The data in flies and human indicate that the MARK3 variant corresponds to a loss of function. We conclude that the identified mutation in MARK3 establishes a new gene-disease link, since it likely causes structural abnormalities during eye development and visual impairment in humans, and that the function of MARK3/par-1 is evolutionarily conserved in eye development.

PMID: 29771303 [PubMed - as supplied by publisher]

Genome-wide sequencing technologies: A primer for paediatricians.

Paediatr Child Health. 2018 May;23(3):191-197

Authors: Hayeems RZ, Boycott KM

Abstract
Genetic testing has been a routine part of paediatic medicine for decades. Over time, the number of genetic tests available for children presenting with features thought to be explained by an underlying genetic aetiology has expanded considerably. Genome-wide sequencing approaches (e.g., whole-exome sequencing, whole-genome sequencing) are now emerging as the most comprehensive approaches to genetic diagnosis that we have seen to date; multiple serial tests that were once required for a child under diagnostic investigation can now be accomplished in a single assay. Moreover, the performance of this single assay appears to be superior to the sum of its parts. Despite this promise, technical, ethical and access-related complexities require considerable attention prior to the implementation of these tools in mainstream paediatrics. To ready paediatricians for the eventual transition to genome-based diagnostics, herein we review both the elements and delivery considerations of this emerging technology.

PMID: 29769805 [PubMed]

Novel variants identified with next-generation sequencing in Polish patients with cone-rod dystrophy.

Mol Vis. 2018;24:326-339

Authors: Wawrocka A, Skorczyk-Werner A, Wicher K, Niedziela Z, Ploski R, Rydzanicz M, Sykulski M, Kociecki J, Weisschuh N, Kohl S, Biskup S, Wissinger B, Krawczynski MR

Abstract
Purpose: The aim of this study was to identify the molecular genetic basis of cone-rod dystrophy in 18 unrelated families of Polish origin. Cone-rod dystrophy is one of the inherited retinal dystrophies, which constitute a highly heterogeneous group of disorders characterized by progressive dysfunction of photoreceptors and retinal pigment epithelium (RPE) cells.
Methods: The study group was composed of four groups of patients representing different Mendelian inheritance of the disease: autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XL), and autosomal recessive or X-linked recessive (AR/XL). The combined molecular strategy included Sanger sequencing of the RPGR-ORF15 gene (three families with XL and three families with the AR/XL mode of inheritance), mutation-specific microarray analysis of the ABCA4 gene (five families with the AR mode of inheritance and two families with the AR/XL mode of inheritance), targeted next-generation sequencing (NGS) of inherited retinal disease-associated (IRD) genes (seven families with the AD mode of inheritance and five families with the AR mode of inheritance), and whole exome sequencing, performed in select families who had been mutation-negative in the analysis with the targeted NGS panel (one family with the AD mode of inheritance, one family with the AR mode of inheritance, and two families with the AR/XL mode of inheritance).
Results: Based on this combined strategy, we managed to identify potentially causative variants in seven out of 18 families with CRD. Five of these variants are novel: c.3142_3143dupAA, p.(Glu1049Argfs*41) in the RPGR-ORF15 gene, two variants: c.1612delT, p.(Trp538Glyfs*15) and c.2389dupG, p.(Ile798Hisfs*20) in the PROM1 gene in one family, c.592A>C, p.(Ser198Arg) in the PRPH2 gene and the variant c.1691A>G, p.(Asp564Gly) in the ATF6 gene that we have already reported to be pathogenic. NGS on the IRD panel allowed the molecular basis of CRD to be identified in four out of 14 families with a total detection rate of 38%. WES allowed identification of the molecular genetic basis of CRD in one family.
Conclusions: This is the first report on the spectrum of disease genes and pathogenic variants causing CRD in the Polish population. The study presents five novel variants identified in four genes and therefore, broadens the spectrum of probable pathogenic variants associated with CRD.

PMID: 29769798 [PubMed - in process]

Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children.

BMC Med Genet. 2018 May 16;19(1):79

Authors: Xu D, Sun C, Zhou Z, Wu B, Yang L, Chang Z, Zhang M, Xi L, Cheng R, Ni J, Luo F

Abstract
BACKGROUND: Mutations in the aggrecan (ACAN) gene can cause short stature (with heterogeneous clinical phenotypes), impaired bone maturation, and large variations in response to growth hormone (GH) treatment. For such cases, long-term longitudinal therapy data from China are still scarce. We report that a previously unknown ACAN gene variant reduces adult height and we analyze the GH response in children from an affected large Chinese family.
METHODS: Two children initially diagnosed with idiopathic short stature (ISS) and a third mildly short child from a large Chinese family presented with poor GH response. Genetic etiology was identified by whole exome sequencing and confirmed via Sanger sequencing. Adult heights were analyzed, and the responses to GH treatment of the proband and two affected relatives are summarized and compared to other cases reported in the literature.
RESULTS: A novel ACAN gene variant c.7465 T > C (p. Gln2364Pro), predicted to be disease causing, was discovered in the children, without evident syndromic short stature; mild bone abnormity was present in these children, including cervical-vertebral clefts and apophyses in the upper and lower thoracic vertebrae. Among the variant carriers, the average adult male and female heights were reduced by - 5.2 and - 3.9 standard deviation scores (SDS), respectively. After GH treatment of the three children, first-year heights increased from 0.23 to 0.33 SDS (cases in the literature: - 0.5 to 0.8 SDS), and the average yearly height improvement was 0.0 to 0.26 SDS (cases in the literature: - 0.5 to 0.9 SDS).
CONCLUSIONS: We report a novel pathogenic ACAN variant in a large Chinese family which can cause severe adult nonsyndromic short stature without evident family history of bone disease. The evaluated cases and the reports from the literature reveal a general trend of gradually diminishing yearly height growth (measured in SDS) over the course of GH treatment in variant-carrying children, highlighting the need to develop novel management regimens.

PMID: 29769040 [PubMed - in process]

Common and rare variants genetic association analysis of cigarettes per day among ever smokers in COPD cases and controls.

Nicotine Tob Res. 2018 May 15;:

Authors: Lutz SM, Frederiksen B, Begum F, McDonald ML, Cho MH, Hobbs B, Parker MM, DeMeo DL, Hersh CP, Eringher M, Young K, Jiang L, Foreman MG, Kinney GL, Make BJ, Lomas DA, Bakke P, Gulsvik A, Crapo JD, Silverman EK, Beaty TH, Hokanson JE, ECLIPSE and COPDGene Investigators

Abstract
Introduction: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown.
Methods: We performed genome-wide association analyses for average cigarettes per day (CPD) across the COPDGene Non-Hispanic White (NHW) (n=6,659) and African American (AA) (n=3,260), GenKOLS (n=1,671), and ECLIPSE (n=1,942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status.
Results: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p=1.78x10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4 p=1.95x10-6; CYP2A7 p=7.50x10-5; CYP2B6 4.04x10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms (SNPs) in chromosome 15q25 were nominally associated in both NHW COPD cases (Beta=0.11, p=5.58x10-4) and controls (Beta=0.12, p=3.86x10-5). For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p=5.2x10-4).
Conclusions: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls.
IMPLICATIONS: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. While the genetic effect sizes for these SNPs on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker.

PMID: 29767774 [PubMed - as supplied by publisher]

DNAJC3 mutation in Thai familial type 2 diabetes mellitus.

Int J Mol Med. 2018 May 14;:

Authors: Kulanuwat S, Tangjittipokin W, Jungtrakoon P, Chanprasert C, Sujjitjoon J, Binnima N, Yenchitsomanus PT, Plengvidhya N

Abstract
Type 2 diabetes mellitus (T2D) is a heterogeneous disease, with certain cases presenting an autosomal dominant type. The rare coding variants of disease‑causing genes in T2D remain mostly unclear. The present study aimed to identify the disease‑causing gene conducting whole exome sequencing in a Thai T2D family with an autosomal dominant transmission of T2D with no evidence of mutations in known maturity‑onset diabetes of the young (MODY) genes. Candidate variants were selected according to certain criteria of mutation prediction programs, followed by segregation analysis with diabetes in the family. The results demonstrated that, of the 68,817 variants obtained, 122 were considered as candidate variants subsequent to the filtering processes. Genotyping of these variants revealed that DnaJ homolog subfamily C member 3 (DNAJC3) p.H238N segregated with diabetes in the family. This mutation was also identified in another proband from the autosomal dominant T2D family without mutation in known MODY genes and was segregated with diabetes. This variant was also identified in 14/1,000 older‑onset T2D patients [minor allele frequency (MAF)=0.007], 2/500 non‑diabetic controls (MAF=0.002) and 3 prediabetic individuals who were previously classified as non‑diabetic controls. In silico mutagenesis and protein modeling of p.H238N revealed changes of the polar contacts across the tetratricopeptide repeat (TPR) motif and TPR subdomains, which may affect the protein tertiary structure. Furthermore, the expression of DNAJC3 H238N protein was 0.68±0.08 fold (P<0.05) lower when compared with that of the wild‑type, possibly due to protein instability. Thus, DNAJC3 p.H238N is likely to be a variant causing diabetes.

PMID: 29767246 [PubMed - as supplied by publisher]

Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness.

Genet Med. 2018 May 15;:

Authors: Stark Z, Schofield D, Martyn M, Rynehart L, Shrestha R, Alam K, Lunke S, Tan TY, Gaff CL, White SM

Abstract
PURPOSE: To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses.
METHODS: We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES).
RESULTS: The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing.
CONCLUSION: These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.

PMID: 29765138 [PubMed - as supplied by publisher]

Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy.

J Med Genet. 2018 May 15;:

Authors: Langer Y, Aran A, Gulsuner S, Abu Libdeh B, Renbaum P, Brunetti D, Teixeira PF, Walsh T, Zeligson S, Ruotolo R, Beeri R, Dweikat I, Shahrour M, Weinberg-Shukron A, Zahdeh F, Baruffini E, Glaser E, King MC, Levy-Lahad E, Zeviani M, Segel R

Abstract
OBJECTIVE: To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy.
METHODS: Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast.
RESULTS: Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids.
CONCLUSION: PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.

PMID: 29764912 [PubMed - as supplied by publisher]

Case Report: Identification of an HNF1B p.Arg527Gln mutation in a Maltese patient with atypical early onset diabetes and diabetic nephropathy.

BMC Endocr Disord. 2018 May 15;18(1):28

Authors: Pace NP, Craus J, Felice A, Vassallo J

Abstract
BACKGROUND: The diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging HNF1β mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy. HNF1β-MODY (MODY5) is an uncommon form of monogenic diabetes that is often complicated by a wide array of congenital morphological anomalies of the urinary tract, including renal cysts. This report expands on the clinical phenotypes that have been described in the context of HNF1β mutations, and is relevant as only isolated cases of diabetic nephropathy in the setting of MODY5 have been reported.
CASE PRESENTATION: An obese Maltese female with non-autoimmune diabetes, microalbuminuria, glomerular hyperfiltration, fatty liver and no renal cysts was studied by whole exome sequencing to investigate potential genes responsible for the proband's phenotype. A rare missense mutation at a highly conserved site in exon 8 of HNF1β was identified (c.1580G > A, NM_000458.3, p.Arg527Gln), with multiple in-silico predictions consistent with pathogenicity. This mutation has not been previously characterised. Additionally, several common susceptibility variants associated with early-onset obesity, polygenic type 2 diabetes and nephropathy were identified in the proband that could impose additional effects on the phenotype, its severity or its clinical course.
CONCLUSION: This report highlights several atypical features in a proband with atypical diabetes associated with an HNF1β missense mutation. It also reinforces the concept that monogenic causes of diabetes could be significant contributors to disease burden in obese individuals with atypical diabetes.

PMID: 29764441 [PubMed - in process]

COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?

BMC Nephrol. 2018 May 16;19(1):114

Authors: Voskarides K, Papagregoriou G, Hadjipanagi D, Petrou I, Savva I, Elia A, Athanasiou Y, Pastelli A, Kkolou M, Hadjigavriel M, Stavrou C, Pierides A, Deltas C

Abstract
BACKGROUND: About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD).
METHODS: Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis.
RESULTS: In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts.
CONCLUSIONS: A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.

PMID: 29764427 [PubMed - in process]

VAReporter: variant reporter for cancer research of massive parallel sequencing.

BMC Genomics. 2018 May 09;19(Suppl 2):86

Authors: Huang PJ, Lee CC, Chiu LY, Huang KY, Yeh YM, Yang CY, Chiu CH, Tang P

Abstract
BACKGROUND: High throughput sequencing technologies have been an increasingly critical aspect of precision medicine owing to a better identification of disease targets, which contributes to improved health care cost and clinical outcomes. In particular, disease-oriented targeted enrichment sequencing is becoming a widely-accepted application for diagnostic purposes, which can interrogate known diagnostic variants as well as identify novel biomarkers from panels of entire human coding exome or disease-associated genes.
RESULTS: We introduce a workflow named VAReporter to facilitate the management of variant assessment in disease-targeted sequencing, the identification of pathogenic variants, the interpretation of biological effects and the prioritization of clinically actionable targets. State-of-art algorithms that account for mutation phenotypes are used to rank the importance of mutated genes through visual analytic strategies. We established an extensive annotation source by integrating a wide variety of biomedical databases and followed the American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation and reporting of sequence variations.
CONCLUSIONS: In summary, VAReporter is the first web server designed to provide a "one-stop" resource for individual's diagnosis and large-scale cohort studies, and is freely available at http://rnd.cgu.edu.tw/vareporter .

PMID: 29764369 [PubMed - in process]

DEPDC5 mutations in familial and sporadic focal epilepsy.

Clin Genet. 2017 Oct;92(4):397-404

Authors: Tsai MH, Chan CK, Chang YC, Yu YT, Chuang ST, Fan WL, Li SC, Fu TY, Chang WN, Liou CW, Chuang YC, Ng CC, Hwang DY, Lim KS

Abstract
BACKGROUND AND AIMS: Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.
MATERIALS AND METHODS: We studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.
RESULTS: We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene.
DISCUSSION AND CONCLUSIONS: Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.

PMID: 28170089 [PubMed - indexed for MEDLINE]

Genotype and phenotype in 12 additional individuals with SATB2-associated syndrome.

Clin Genet. 2017 Oct;92(4):423-429

Authors: Zarate YA, Kalsner L, Basinger A, Jones JR, Li C, Szybowska M, Xu ZL, Vergano S, Caffrey AR, Gonzalez CV, Dubbs H, Zackai E, Millan F, Telegrafi A, Baskin B, Person R, Fish JL, Everman DB

Abstract
SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.

PMID: 28139846 [PubMed - indexed for MEDLINE]

Whole Exome Sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.

Int J Cancer. 2018 May 15;:

Authors: Paumard-Hernández B, Calvete O, Inglada Pérez L, Tejero H, Al-Shahrour F, Pita G, Barroso A, Triviño JC, Urioste M, Valverde C, González Billalabeitia E, Quiroga V, Rodríguez Moreno JF, Fernández Aramburo A, López C, Maroto P, Sastre J, Juan Fita MJ, Duran I, Lorenzo-Lorenzo I, Iranzo P, García Del Muro X, Ros S, Zambrana F, Autran AM, Benítez J

Abstract
Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28 y) than sporadic cases (33 y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) vs controls (almost 1170), and three of them [PLEC (OR=6.28, p-value=6.42 x 10-23) (p.Arg2016Trp), EXO5 (OR=3.37, p-value=4.82 x 10-09) (p.Arg344AlafsTer10) and DNAH7 (OR=1.64, p-value=0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT. This article is protected by copyright. All rights reserved.

PMID: 29761480 [PubMed - as supplied by publisher]

Microcephaly, short stature, and limb abnormality disorder due to novel autosomal biallelic DONSON mutations in two German siblings.

Eur J Hum Genet. 2018 May 14;:

Authors: Schulz S, Mensah MA, de Vries H, Fröber R, Romeike B, Schneider U, Borte S, Schindler D, Kentouche K

Abstract
Recently, variants in DONSON have been reported to cause different disorders of the microcephalic primordial dwarfism spectrum. Using whole-exome sequencing, we identified two novel, compound heterozygous DONSON variants in a pair of siblings, one of whom was previously diagnosed with Fanconi anemia. This occurred because the present cases exhibited clinical findings in addition to those of the microcephalic primordial dwarfism disorder, including severe limb malformations. These findings suggest that the DONSON and Fanconi anemia proteins could have supplementary roles in developmental processes as they have in the maintenance of genomic integrity, resulting in related disease phenotypes.

PMID: 29760432 [PubMed - as supplied by publisher]