Whole Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease.

Am J Respir Cell Mol Biol. 2018 Jun 27;:

Authors: Prokopenko D, Sakornsakolpat P, Loehlein Fier H, Qiao D, Parker MM, McDonald MN, Manichaikul A, Rich SS, Barr RG, Williams CJ, Brantly ML, Lange C, Beaty TH, Crapo JD, Silverman EK, Cho MH, COPDGene Investigators, NHLBI TOPMed Investigators

Abstract
RATIONALE: Genome-wide association studies (GWAS) have identified common variants associated with chronic obstructive pulmonary disease (COPD). Whole-genome sequencing (WGS) offers comprehensive coverage of the entire genome compared with genotyping arrays or exome sequencing.
OBJECTIVES: We hypothesized that WGS in subjects with severe COPD and smoking controls with normal pulmonary function would allow us to identify novel genetic determinants of COPD.
METHODS: We sequenced 821 severe COPD cases and 973 controls from the COPDGene and Boston Early-Onset COPD studies, including both non-Hispanic white (NHW) and African Americans (AA). We performed single-variant and grouped-variant analyses, and additionally assessed the overlap of variants between sequencing and array-based imputation.
RESULTS: Our most associated variant was in a known region near HHIP (combined p=1.6x10-9); additional variants approaching genome-wide significance included previously described regions in CHRNA5, TNS1, and SERPINA6/SERPINA1. None of our associations were clearly driven by rare variants, and we found minimal evidence of replication of genes identified by previously reported smaller sequencing studies. With WGS we identified >20 million new variants, not seen with imputation, including >10,000 of potential importance in previously identified COPD GWAS regions.
CONCLUSIONS: Whole-genome sequencing in severe COPD identifies a large number of potentially important functional variants, with the strongest associations being in known COPD risk loci, including HHIP and SERPINA1 (AA). Larger sample sizes will be needed to identify associated variants in novel regions of the genome.

PMID: 29949718 [PubMed - as supplied by publisher]

Hepatosplenomegaly, pneumopathy, bone changes and fronto-temporal dementia: Niemann-Pick type B and SQSTM1-associated Paget's disease in the same individual.

J Bone Miner Metab. 2018 Jun 14;:

Authors: Voinea C, Gonzalez Rodriguez E, Beigelman-Aubry C, Leroy V, Aubry-Rozier B, Campos-Xavier B, Ballhausen D, Lazor R, Barbey F, Bonafé L, Superti-Furga A, Tran C

Abstract
Data from exome sequencing show that a proportion of individuals in whom a genetic disorder is suspected turn out to have not one, but two to four distinct ones. This may require an evolution in our diagnostic attitude towards individuals with complex disorders. We report a patient with splenomegaly, pneumopathy, bone changes and fronto-temporal dementia (FTD). "Sea-blue histiocytes" in his bone marrow pointed to a lysosomal storage disease. Homozygosity for a pathogenic mutation in the SMPD1 gene confirmed Niemann-Pick disease type B (NPD-B). Mild cognitive impairment and abnormal brain FDG PET were consistent with FTD. We initially tried to fit the skeletal and neurologic phenotype into the NPD-B diagnosis. However, additional studies revealed a pathogenic mutation in the SQSTM1 gene. Thus, our patient had two distinct diseases; NPD-B, and Paget's disease of bone with FTD. The subsequent finding of a mutation in SQSTM1 gene ended our struggle to explain the combination of findings by a singular "unifying" diagnosis and allowed us to make specific therapeutic decisions. SQSTM1 mutations have been reported in association with FTD, possibly because of defective autophagy. Bisphosphonates may be beneficial for PDB, but since they are known to inhibit acid sphingomyelinase activity, we refrained from using them in this patient. While the principle of looking for unifying diagnosis remains valid, physicians should consider the possibility of co-existing multiple diagnoses when clinical features are difficult to explain by a single one. Accurate diagnostic work-up can guide genetic counseling but also lead to better medical management.

PMID: 29948344 [PubMed - as supplied by publisher]

A novel LMNA nonsense mutation causes two distinct phenotypes of cardiomyopathy with high risk of sudden cardiac death in a large five-generation family.

Europace. 2018 Jun 26;:

Authors: Glöcklhofer CR, Steinfurt J, Franke G, Hoppmann A, Glantschnig T, Perez-Feliz S, Alter S, Fischer J, Brunner M, Rainer PP, Köttgen A, Bode C, Odening KE

Abstract
Aims: Characterization of the cardiac phenotype associated with the novel LMNA nonsense mutation c.544C>T, p.Q182*, which we have identified in a large five-generation family.
Methods and results: A family tree was constructed. Clinical data [arrhythmia, syncope, sudden cardiac death (SCD), New York Heart Association (NYHA) class] were collected from living and deceased family members. DNA of 23 living family members was analysed for mutations in LMNA. Additionally, dilated cardiomyopathy multi-gene-panel testing and whole exome sequencing were performed in some family members to identify potential phenotype-modifiers. In this five-generation family (n = 65), 17 SCDs occurred at 49.3 ± 10.0 years. Furthermore, we identified eight additional mutation-carriers, seven symptomatic (44 ± 13 years), and one asymptomatic (44 years). First signs of disease [sinus bradycardia with atrioventricular (AV)-block I°] occurred at 36.5 ± 8.1 years. Paroxysmal atrial fibrillation (AF) (onset at 41.8 ± 5.7 years) rapidly progressed to permanent AF (46.2 ± 9.8 years). Subsequently, AV-conduction worsened, syncope, pacemaker-dependence, and non-sustained ventricular tachycardia (43.3 ± 8.2 years) followed. Ventricular arrhythmia caused SCD in patients without implantable cardioverter-defibrillator (ICD). Patients protected by ICD developed rapidly progressive heart failure (45.2 ± 10.6 years). A different phenotype was seen in a sub-family in three patients with early onset of rapidly decompensating heart failure and only minor prior arrhythmia-related symptoms. One patient received high-urgency heart transplantation (HTX) at 32 years, while two died prior to HTX. One of them developed lethal peripartum-associated heart failure. Possible disease-modifiers were identified in this 'heart failure sub-family'.
Conclusion: The novel LMNA nonsense mutation c.544C>T causes a severe arrhythmogenic phenotype manifesting with high incidence of SCD in most patients; and in one sub-family, a distinct phenotype with fast progressing heart failure, indicating the need for early consideration of ICD-implantation and listing for heart-transplantation.

PMID: 29947763 [PubMed - as supplied by publisher]

Mitochondrial disease: learning from Charlie's lesson, trying to cure, trying much more to care.

Future Cardiol. 2018 Jun 27;:

Authors: Limongelli G, Wahbi K

PMID: 29947560 [PubMed - as supplied by publisher]

Fetal exome sequencing: yield and limitations in a single tertiary center.

Ultrasound Obstet Gynecol. 2018 Jun 26;:

Authors: Daum H, Meiner V, Elpeleg O, Harel T

Abstract
OBJECTIVE: To explore the indications and diagnostic outcomes of fetal exomes in a single referral center.
METHODS: 77 unrelated fetal samples underwent exome sequencing between 2012-2017. Indications, turnaround time, diagnostic rates, and pregnancy outcomes were investigated.
RESULTS: The most common indication for fetal exome sequencing was multiple malformations (21/77, 27%), followed by isolated brain malformations (15/77, 19%). Twelve fetuses (15%) were referred for isolated increased nuchal translucency (IINT). Exome analysis was diagnostic for 16 fetuses (21%); when sub-classified to fetal malformations vs. IINT it became clear that exome analysis did not reveal any known or probable pathogenic variants in IINT whereas among the remaining fetuses, a molecular diagnosis was reached in 16/65 (25%). Proband-only cases received a diagnosis more often than trio exomes.
CONCLUSION: Exome sequencing has the potential to provide molecular diagnoses in cases where conventional prenatal cytogenetic testing is negative. A referral bias of consanguineous cases could account for the high diagnostic rate for proband-only sequencing. Syndrome-specific prognostic information enables parents to make informed decisions, whereas challenges include time limitations and variant interpretation in the setting of non-specific fetal findings. As we report only established disease-gene associations, further segregation and functional studies in a research setting are expected to significantly increase the diagnostic yield. This article is protected by copyright. All rights reserved.

PMID: 29947050 [PubMed - as supplied by publisher]

[Rational use of genetic tests in internal medicine : Possibilities and limitations of next generation sequencing diagnostics].

Internist (Berl). 2018 Jun 26;:

Authors: Elbracht M, Meyer R, Eggermann T, Kurth I

Abstract
BACKGROUND: New methods of molecular genetic diagnostics enable a more comprehensive genetic analysis of patients.
OBJECTIVES: Rational use and benefits of molecular genetic testing in patients with various internal diseases.
METHOD: Evaluation of topic-related literature, discussion of own experiences, as well as consideration of current guidelines.
RESULTS: New genetic tests, such as next generation sequencing (NGS), improve the diagnosis of hereditary diseases; however, the use of this technology also leads to additional findings, which must be carefully considered.
CONCLUSION: The rational use of genetic tests is a benefit for patients and can significantly influence the prevention and treatment of a disease. The increasing complexity of genetic findings requires interdisciplinary approaches involving human genetics, internal medicine, and other disciplines.

PMID: 29946883 [PubMed - as supplied by publisher]

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage.

Neuroimage Clin. 2018;19:848-857

Authors: Faber I, Martinez ARM, de Rezende TJR, Martins CR, Martins MP, Lourenço CM, Marques W, Montecchiani C, Orlacchio A, Pedroso JL, Barsottini OGP, Lopes-Cendes Í, França MC

Abstract
SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

PMID: 29946510 [PubMed - in process]

Two Novel TEX15 Mutations in a Family with Nonobstructive Azoospermia.

Gynecol Obstet Invest. 2017;82(3):283-286

Authors: Colombo R, Pontoglio A, Bini M

Abstract
AIM: Genetic investigations explain only a small percentage of cases of nonobstructive azoospermia (NOA), a condition that affects up to 2% of infertile couples. This study aimed to identify further genomic variants that are associated with primary spermatogenic failure within the testis.
METHODS: One family with 2 infertile siblings affected by NOA was genotyped by whole-exome sequencing. DNA variants were filtered based on quality score, allele frequency, and functional roles of genes in spermatogenesis.
RESULTS: Both NOA males were compound heterozygotes for a nonsense mutation and a single nucleotide deletion leading to premature stop codons in the TEX15 gene (c.2419A>T, p.Lys807*, and c.3040delT, p.Ser1014Leufs*5, respectively). The single mutations were identified only on one allele in 6 family members, including 3 fertile males who conceived naturally.
CONCLUSION: This is the second reported case of a TEX15 deleterious mutation cosegregating with NOA in a family in which the infertile phenotype is reminiscent of the one observed in the TEX15-knockout mouse, confirming that TEX15 plays a critical role in normal spermatogenesis and its defects may be responsible for a number of NOA cases.

PMID: 28355598 [PubMed - indexed for MEDLINE]

Inhibition of BET bromodomain proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a biologically aggressive variant of Endometrial Cancer.

Clin Cancer Res. 2018 Jun 25;:

Authors: Bonazzoli E, Predolini F, Cocco E, Bellone S, Altwerger G, Menderes G, Zammataro L, Bianchi A, Pettinella F, Riccio F, Han C, Yadav G, Lopez S, Manzano A, Manara P, Buza N, Hui P, Wong S, Litkouhi B, Ratner E, Silasi DA, Huang GS, Azodi M, Schwartz PE, Schlessinger J, Santin AD

Abstract
PURPOSE: Uterine-serous-carcinoma (USC) is a rare and aggressive variant of endometrial cancer. Whole-exome-sequencing (WES) studies have recently reported c-Myc gene amplification in large number of USC suggesting c-Myc as a potential therapeutic target. We investigated the activity of novel BET bromodomain inhibitors (GS-5829 and GS-626510, Gilead-Science-Inc.) and JQ1 against primary USC-cultures and USC-xenografts.
EXPERIMENTAL DESIGN: We evaluated c-Myc expression by qRT-PCR in a total of 45 USC including fresh-frozen-tumor-tissues and primary USC-cell-lines. We also performed immunohistochemistry (IHC) and Western-Blot experiments in 8 USC tumors. USC cultures were evaluated for sensitivity to GS-5829, GS-626510 and JQ1 in-vitro using proliferation, viability and apoptosis-assays. Finally, the in-vivo activity of GS-5829, GS-626510 and JQ1 was studied in USC-ARK1 and USC-ARK2 mouse-xenografts.
RESULTS: Fresh-frozen USC and primary USC cell-lines overexpressed c-Myc when compared to normal tissues (p =0.0009 and =0.0083, respectively). High c-Myc expression was found in 7 of 8 of primary USC cell lines tested by qRT-PCR and 5 of 8 tested by IHC. In-vitro experiments demonstrated high sensitivity of USC cell-lines to the exposure to GS-5829, GS-626510 and JQ1 with BET-inhibitors causing a dose-dependent decrease in the phosphorylated levels of c-Myc and a dose-dependent increase in caspase activation (apoptosis). In comparative in-vivo experiments GS-5829 and/or GS-626510 were found more effective than JQ1 at the concentrations/doses used in decreasing tumor-growth in both USC-ARK1 and USC-ARK2 mouse-xenograft-models.
CONCLUSIONS: GS-5829 and GS-626510 may represent novel, highly effective therapeutics agents against recurrent/chemotherapy resistant USC overexpressing c-Myc. Clinical studies with GS-5829 in USC-patients harboring chemotherapy-resistant disease are warranted.

PMID: 29941483 [PubMed - as supplied by publisher]

Nonsynonymous Variants in PAX4 and GLP1R are Associated with Type 2 Diabetes in an East Asian Population.

Diabetes. 2018 Jun 25;:

Authors: Kwak SH, Chae J, Lee S, Choi S, Koo BK, Yoon JW, Park JH, Cho B, Moon MK, Lim S, Cho YM, Moon S, Kim YJ, Han S, Hwang MY, Cho YS, Lee MS, Jang HC, Kang HM, Park T, Cho NH, Kim K, Kim JI, Park KS

Abstract
We investigated ethnicity specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole exome sequencing in 917 T2D cases and controls and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in additional 13,122 participants. Single variant and gene-based association for T2D were analysed. A total of 728,838 variants were identified by whole exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P=4.47×10-16, and OR 0.84, P=3.55×10-8, respectively). Another variant at PAX4 192 codon, Arg192Ser was nominally associated with T2D (OR 1.62, P=5.18×10-4). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In non-diabetic controls, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P=1.0×10-4). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.

PMID: 29941447 [PubMed - as supplied by publisher]

TREX1 Mutation Causing Autosomal Dominant Thrombotic Microangiopathy and CKD-A Novel Presentation.

Am J Kidney Dis. 2018 Jun 22;:

Authors: Gulati A, Bale AE, Dykas DJ, Bia MJ, Danovitch GM, Moeckel GW, Somlo S, Dahl NK

Abstract
Renal thrombotic microangiopathy (TMA) involves diverse causes and clinical presentations. Genetic determinants causing alternate pathway complement dysregulation underlie a substantial proportion of cases. In a significant proportion of TMAs, no defect in complement regulation is identified. Mutations in the major mammalian 3' DNA repair exonuclease 1 (TREX1) have been associated with autoimmune and cerebroretinal vasculopathy syndromes. Carboxy-terminal TREX1 mutations that result in only altered localization of the exonuclease protein with preserved catalytic function cause microangiopathy of the brain and retina, termed retinal vasculopathy and cerebral leukodystrophy (RVCL). Kidney involvement reported with RVCL usually accompanies significant brain and retinal microangiopathy. We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.

PMID: 29941221 [PubMed - as supplied by publisher]

Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.

PLoS Genet. 2018 04;14(4):e1007321

Authors: Hendrickx G, Borra VM, Steenackers E, Yorgan TA, Hermans C, Boudin E, Waterval JJ, Jansen IDC, Aydemir TB, Kamerling N, Behets GJ, Plumeyer C, D'Haese PC, Busse B, Everts V, Lammens M, Mortier G, Cousins RJ, Schinke T, Stokroos RJ, Manni JJ, Van Hul W

Abstract
Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.

PMID: 29621230 [PubMed - indexed for MEDLINE]

Genetic Characterization of Adenoid Cystic Carcinoma of the Minor Salivary Glands: A Potential Familial Occurrence in First-Degree Relatives.

Head Neck Pathol. 2017 Dec;11(4):546-551

Authors: Channir HI, van Overeem Hansen T, Andreasen S, Yde CW, Kiss K, Charabi BW

Abstract
Adenoid cystic carcinoma (AdCC) is a malignant salivary gland tumor. To date, no cases of AdCC in first-degree relatives have been reported in the literature. We present a 50-year-old female (Case 1) and this patients' father (Case 2), both of whom were diagnosed with AdCC of the minor salivary glands. Histology of Case 1 demonstrated a tubulocribriform AdCC whereas Case 2 primarily was an AdCC of solid type. Both cases harbored the MYB-NFIB gene fusion as demonstrated by FISH and RNA-sequencing. After filtering and selection of putative deleterious variants, whole exome sequencing identified 18 germline variants in common between Case 1 and Case 2. However, none of the variants were associated with AdCC or other head and neck cancers. To our knowledge, we present the first potential case of familial AdCC. The presented genetic data may contribute to further investigations of the underlying genetic mechanisms for AdCC susceptibility.

PMID: 28210977 [PubMed - indexed for MEDLINE]

PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum.

Neuropediatrics. 2018 Jun 25;:

Authors: Alhaddad B, Schossig A, Haack TB, Kovács-Nagy R, Braunisch MC, Makowski C, Senderek J, Vill K, Müller-Felber W, Strom TM, Krabichler B, Freisinger P, Deshpande C, Polster T, Wolf NI, Desguerre I, Wörmann F, Rötig A, Ahting U, Kopajtich R, Prokisch H, Meitinger T, Feichtinger RG, Mayr JA, Jungbluth H, Hubmann M, Zschocke J, Distelmaier F, Koch J

Abstract
BACKGROUND:  Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations.
METHODS:  Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.
RESULTS:  We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene.
CONCLUSIONS:  PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

PMID: 29940663 [PubMed - as supplied by publisher]

Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation.

Clin Genet. 2018 Jun 25;:

Authors: Pilch J, Koppolu AA, Walczak A, Pienkowski VAM, Biernacka A, Skiba P, Machnik-Broncel J, Gasperowicz P, Kosińska J, Rydzanicz M, Emich-Widera E, Płoski R

Abstract
The HNRNPH2-associated disease (Mental retardation, X-linked, syndromic, Bain type (MRXSB, MIM#300986) is caused by de novo mutations in the X-linked HNRNPH2 gene. MRXSB has been described in 6 female patients with dysmorphy, developmental delay, intellectual disability, autism, hypotonia and seizures. The reported HNRNPH2 mutations were clustered in the small domain encoding nuclear localization signal; in particular, the p.Arg206Trp was found in 4 independent de novo events. HNRNPH1 is a conserved autosomal paralogue of HNRNPH2 with a similar function in regulation of pre-mRNAs splicing but so far it has not been associated with human disease. We describe a boy with a disease similar to MRXSB in whom a novel de novo mutation c.616C>T (p.Arg206Trp) in HNRNPH1 was found (i.e. the exact paralogue of the recurrent HNRNPH2 mutation). We propose that defective function of HNRNPH2 and HNRNPH1 nuclear localization signal has similar clinical consequences. An important difference between the two diseases is that the HNRNPH1 associated syndrome may occur in boys (as in the case of our proband) which is well explained by the autosomal (chr.5q35.3) rather than X-linked localization of the HNRNPH2 gene. This article is protected by copyright. All rights reserved.

PMID: 29938792 [PubMed - as supplied by publisher]

The landscape of somatic mutation in sporadic Chinese colorectal cancer.

Oncotarget. 2018 Jun 08;9(44):27412-27422

Authors: Liu Z, Yang C, Li X, Luo W, Roy B, Xiong T, Zhang X, Yang H, Wang J, Ye Z, Chen Y, Song J, Ma S, Zhou Y, Yang M, Fang X, Du J

Abstract
Colorectal cancer is the fifth prevalent cancer in China. Nevertheless, a large-scale characterization of Chinese colorectal cancer mutation spectrum has not been carried out. In this study, we have performed whole exome-sequencing analysis of 98 patients' tumor samples with matched pairs of normal colon tissues using Illumina and Complete Genomics high-throughput sequencing platforms. Canonical CRC somatic gene mutations with high prevalence (>10%) have been verified, including TP53, APC, KRAS, SMAD4, FBXW7 and PIK3CA. PEG3 is identified as a novel frequently mutated gene (10.6%). APC and Wnt signaling exhibit significantly lower mutation frequencies than those in TCGA data. Analysis with clinical characteristics indicates that APC gene and Wnt signaling display lower mutation rate in lymph node positive cancer than negative ones, which are not observed in TCGA data. APC gene and Wnt signaling are considered as the key molecule and pathway for colorectal cancer initiation, and these findings greatly undermine their importance in tumor progression for Chinese patients. Taken together, the application of next-generation sequencing has led to the determination of novel somatic mutations and alternative disease mechanisms in colorectal cancer progression, which may be useful for understanding disease mechanism and personalizing treatment for Chinese patients.

PMID: 29937994 [PubMed]

Circulating Tumour DNA Analysis for Tumour Genome Characterisation and Monitoring Disease Burden in Extramedullary Multiple Myeloma.

Int J Mol Sci. 2018 Jun 24;19(7):

Authors: Mithraprabhu S, Sirdesai S, Chen M, Khong T, Spencer A

Abstract
Mutational characterisation in extramedullary multiple myeloma (EM-MM) patients is challenging due to inaccessible EM plasmacytomas, unsafe nature of multiple biopsies and the spatial and temporal genomic heterogeneity apparent in MM (Graphical abstract). Conventional monitoring of disease burden is through serum markers and PET-CT, however these modalities are sometimes inadequate (serum markers), not performed in a timely manner (PET-CT) and uninformative for identifying mutations driving disease progression. DNA released into the blood by tumour cells (ctDNA) contains the predominant clones derived from the multiple disease foci. Blood-derived ctDNA can, therefore, provide a holistic illustration of the major drivers of disease progression. In this report, the utility of ctDNA, as an adjunct to currently available modalities in EM-MM, is presented for a patient with EM and oligosecretory (OS) disease. Whole exome sequencing of contemporaneously acquired tumour tissue and matched ctDNA samples revealed the presence of spatial and temporal genetic heterogeneity and the identification of pathways associated with drug resistance. Longitudinal monitoring of plasma samples revealed that ctDNA can be utilised to define the dynamic clonal evolution co-existent with disease progression and as an adjunct non-invasive marker of tumour burden.

PMID: 29937522 [PubMed - in process]

Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology.

Eur Urol. 2018 Jun 20;:

Authors: Loveday C, Law P, Litchfield K, Levy M, Holroyd A, Broderick P, Kote-Jarai Z, Dunning AM, Muir K, Peto J, Eeles R, Easton DF, Dudakia D, Orr N, Pashayan N, UK Testicular Cancer Collaboration, The PRACTICAL Consortium, Reid A, Huddart RA, Houlston RS, Turnbull C

Abstract
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene.
PATIENT SUMMARY: To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general.

PMID: 29935977 [PubMed - as supplied by publisher]

Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families.

Congenit Anom (Kyoto). 2018 Jun 23;:

Authors: Rahman SB, Mir A, Ahmad N, Haider SH, Malik SA, Nasir M

Abstract
Non-bullous congenital ichthyosiform erythroderma (NCIE) is characterized by skin scaling with erythema. In this study, two Pakistani families with NCIE are genetically characterized through Whole Exome and Sanger sequencing to identify molecular basis of the disease. We identified a nonsense homozygous c.2026C>T mutation of ALOXE3, causing premature termination of the eLOX3 protein (p.Q676X). In silico studies predicted impaired enzymatic activity of the premature truncated eLOX3, leading to abnormal synthesis of specific hepoxilin derivatives, essential for epidermal barrier formation. It is the first ever study reporting homozygotes of p.Q676X mutation in ethnically distinct two Pakistani families; otherwise, heterozygotes of the said mutation have been reported in South Asian population only. Hence, mutation seems to be region-specific and may be useful for molecular diagnosis of NCIE. Moreover, our findings should help in genetic counseling and career screening. This article is protected by copyright. All rights reserved.

PMID: 29935003 [PubMed - as supplied by publisher]

Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy.

Neuromuscul Disord. 2018 May 21;:

Authors: Findlay AR, Harms MB, Pestronk A, Weihl CC

Abstract
Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246Thr homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies.

PMID: 29934118 [PubMed - as supplied by publisher]