Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2).

Am J Med Genet A. 2018 Oct 22;:

Authors: Boczek NJ, Lahner CA, Nguyen TM, Ferber MJ, Hasadsri L, Thorland EC, Niu Z, Gavrilova RH

Abstract
Wolf-Hirschhorn syndrome (WHS) is a microdeletion syndrome characterized by distinctive facial features consisting of "Greek warrior helmet" appearance, prenatal and postnatal growth deficiency, developmental disability, and seizures. This disorder is caused by heterozygous deletions on chromosome 4p16.3 often identified by cytogenetic techniques. Many groups have attempted to identify the critical region within this deletion to establish which genes are responsible for WHS. Herein, clinical whole exome sequencing (WES) was performed on a child with developmental delays, mild facial dysmorphisms, short stature, failure to thrive, and microcephaly, and revealed a de novo frameshift variant, c.1676_1679del (p.Arg559Tfs*38), in WHSC1 (NSD2). While WHSC1 falls within the WHS critical region, individuals with only disruption of this gene have only recently been described in the literature. Loss-of-function de novo variations in WHSC1 were identified in large developmental delay, autism, diagnostic, and congenital cardiac cohorts, as well as recent case reports, suggesting that de novo loss-of-function WHSC1 variants may be related to disease. These findings, along with our patient suggest that loss-of-function variation in WHSC1 may lead to a mild form of Wolf-Hirschhorn syndrome, and also may suggest that the developmental delays, facial dysmorphisms, and short stature seen in WHS may be due to disruption of WHSC1 gene.

PMID: 30345613 [PubMed - as supplied by publisher]

Whole-exome sequencing in maya indigenous families: variant in PPP1R3A is associated with type 2 diabetes.

Mol Genet Genomics. 2018 Oct;293(5):1205-1216

Authors: Sánchez-Pozos K, Ortíz-López MG, Peña-Espinoza BI, de Los Ángeles Granados-Silvestre M, Jiménez-Jacinto V, Verleyen J, Tekola-Ayele F, Sanchez-Flores A, Menjivar M

Abstract
It has been presumed that increased susceptibility in Mexicans to type 2 diabetes (T2D) is attributed to the Native American genetic ancestry. Nonetheless, it is not known if there are private genetic variants that confer susceptibility to develop T2D in our population. The Maya indigenous group has the highest proportion of Native American ancestry (98%) which makes it a representative group of the original peoples of Mexico. Thus, the aim of the present study is to identify new genetic variants associated with T2D in Maya families. Whole-exome sequencing was performed on DNA samples from Maya families with a third-generation family history of T2D only in one parental line. Four variants were identified for APOB, PPP1R3A, TPPP2, and GPR1 genes, and were further tested for association with T2D in 600 unrelated Maya in a case-control study. For the first time, rs1799999 in PPP1R3A was associated with risk of T2D in Mayan Mexican individuals (OR = 1.625, P = 0.014). Interestingly, carriers of rs1799999 presented increased values of HOMA-IR. In addition, rs1801702 in APOB was associated with total cholesterol and LDL-C (P = 0.019 and P = 0.020, respectively) in normoglycemic individuals; rs3732083 in GPR1 with HOMA-IR (P = 0.016) and rs9624 in TPPP2 with total cholesterol and triglycerides (P = 0.002 and P = 0.005, respectively) in T2D subjects. Overall, these findings support the idea that there are other genetic variants yet to be described, involved in T2D development in Maya population, being insulin resistance and lipid metabolism the main mechanisms implicated. Thus, these results can contribute to the understanding of diabetes genetic background in Mexican population.

PMID: 29948331 [PubMed - indexed for MEDLINE]

Consanguineous familial study revealed biallelic FIGLA mutation associated with premature ovarian insufficiency.

J Ovarian Res. 2018 Jun 18;11(1):48

Authors: Chen B, Li L, Wang J, Li T, Pan H, Liu B, Zhou Y, Cao Y, Wang B

Abstract
BACKGROUND: To dissect the genetic alteration in two sisters with premature ovarian insufficiency (POI) from a consanguineous family.
METHODS: Whole-exome sequencing technology was used in the POI proband, bioinformatics analysis was carried out to identify the potential genetic cause in this pedigree. Sanger sequencing analyses were performed to validate the segregation of the variant within the pedigree. In silico analysis was also used to predict the effect and pathogenicity of the variant.
RESULTS: Whole-exome sequencing analysis identified novel and rare homozygous mutation associated with POI, namely mutation in FIGLA (c.2 T > C, start codon shift). This homozygous mutation was also harbored by the proband's sister with POI and was segregated within the consanguineous pedigree. The mutation in the start codon of the FIGLA gene alters the open reading frame, leading to a FIGLA knock-out like phenotype.
CONCLUSIONS: Biallelic mutations in FIGLA may be the cause of POI. This study will aid researchers and clinicians in genetic counseling of POI and provides new insights into understanding the mode of genetic inheritance of FIGLA mutations in POI pathology.

PMID: 29914564 [PubMed - indexed for MEDLINE]

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing.

Sci Rep. 2017 01 11;7:40319

Authors: Wang Y, Du X, Bin R, Yu S, Xia Z, Zheng G, Zhong J, Zhang Y, Jiang YH, Wang Y

Abstract
Genetic factors play a major role in the etiology of epilepsy disorders. Recent genomics studies using next generation sequencing (NGS) technique have identified a large number of genetic variants including copy number (CNV) and single nucleotide variant (SNV) in a small set of genes from individuals with epilepsy. These discoveries have contributed significantly to evaluate the etiology of epilepsy in clinic and lay the foundation to develop molecular specific treatment. However, the molecular basis for a majority of epilepsy patients remains elusive, and furthermore, most of these studies have been conducted in Caucasian children. Here we conducted a targeted exome-sequencing of 63 trios of Chinese epilepsy families using a custom-designed NGS panel that covers 412 known and candidate genes for epilepsy. We identified pathogenic and likely pathogenic variants in 15 of 63 (23.8%) families in known epilepsy genes including SCN1A, CDKL5, STXBP1, CHD2, SCN3A, SCN9A, TSC2, MBD5, POLG and EFHC1. More importantly, we identified likely pathologic variants in several novel candidate genes such as GABRE, MYH1, and CLCN6. Our results provide the evidence supporting the application of custom-designed NGS panel in clinic and indicate a conserved genetic susceptibility for epilepsy between Chinese and Caucasian children.

PMID: 28074849 [PubMed - indexed for MEDLINE]

Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth.

BMC Genet. 2018 Oct 20;19(1):94

Authors: Hamvas A, Feng R, Bi Y, Wang F, Bhattacharya S, Mereness J, Kaushal M, Cotten CM, Ballard PL, Mariani TJ, PROP Investigators

Abstract
BACKGROUND: Previous studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, findings with genome-wide significance have been rare, and not replicated. We hypothesized that whole exome sequencing (WES) of premature subjects with extremely divergent phenotypic outcomes could facilitate the identification of genetic variants or gene networks contributing disease risk.
RESULTS: The Prematurity and Respiratory Outcomes Program (PROP) recruited a cohort of > 765 extremely preterm infants for the identification of markers of respiratory morbidity. We completed WES on 146 PROP subjects (85 affected, 61 unaffected) representing extreme phenotypes of early respiratory morbidity. We tested for association between disease status and individual common variants, screened for rare variants exclusive to either affected or unaffected subjects, and tested the combined association of variants across gene loci. Pathway analysis was performed and disease-related expression patterns were assessed. Marginal association with BPD was observed for numerous common and rare variants. We identified 345 genes with variants unique to BPD-affected preterm subjects, and 292 genes with variants unique to our unaffected preterm subjects. Of these unique variants, 28 (19 in the affected cohort and 9 in unaffected cohort) replicate a prior WES study of BPD-associated variants. Pathway analysis of sets of variants, informed by disease-related gene expression, implicated protein kinase A, MAPK and Neuregulin/epidermal growth factor receptor signaling.
CONCLUSIONS: We identified novel genes and associated pathways that may play an important role in susceptibility/resilience for the development of lung disease in preterm infants.

PMID: 30342483 [PubMed - in process]

Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features.

Gastroenterology. 2018 Oct 17;:

Authors: Omori Y, Ono Y, Tanino M, Karasaki H, Yamaguchi H, Furukawa T, Enomoto K, Ueda J, Sumi A, Katayama J, Muraki M, Taniue K, Takahashi K, Ambo Y, Shinohara T, Nishihara H, Sasajima J, Maguchi H, Mizukami Y, Okumura T, Tanaka S

Abstract
BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about mechanism of progression. This makes it a challenge to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses.
METHODS: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs; 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors.
RESULTS: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes.
CONCLUSIONS: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs-we call these the sequential, branch-off, and de novo subtypes. Subtypes might associate with clinical and pathology features and be used to select surveillance programs for patients with IPMNs.

PMID: 30342036 [PubMed - as supplied by publisher]

A de novo variant in ADGRL2 suggests a novel mechanism underlying the previously undescribed association of extreme microcephaly with severely reduced sulcation and rhombencephalosynapsis.

Acta Neuropathol Commun. 2018 Oct 19;6(1):109

Authors: Vezain M, Lecuyer M, Rubio M, Dupé V, Ratié L, David V, Pasquier L, Odent S, Coutant S, Tournier I, Trestard L, Adle-Biassette H, Vivien D, Frébourg T, Gonzalez BJ, Laquerrière A, Saugier-Veber P

Abstract
Extreme microcephaly and rhombencephalosynapsis represent unusual pathological conditions, each of which occurs in isolation or in association with various other cerebral and or extracerebral anomalies. Unlike microcephaly for which several disease-causing genes have been identified with different modes of inheritance, the molecular bases of rhombencephalosynapsis remain unknown and rhombencephalosynapsis presents mainly as a sporadic condition consistent with de novo dominant variations. We report for the first time the association of extreme microcephaly with almost no sulcation and rhombencephalosynapsis in a fœtus for which comparative patient-parent exome sequencing strategy revealed a heterozygous de novo missense variant in the ADGRL2 gene. ADGRL2 encodes latrophilin 2, an adhesion G-protein-coupled receptor whose exogenous ligand is α-latrotoxin. Adgrl2 immunohistochemistry and in situ hybridization revealed expression in the telencephalon, mesencephalon and rhombencephalon of mouse and chicken embryos. In human brain embryos and fœtuses, Adgrl2 immunoreactivity was observed in the hemispheric and cerebellar germinal zones, the cortical plate, basal ganglia, pons and cerebellar cortex. Microfluorimetry experiments evaluating intracellular calcium release in response to α-latrotoxin binding showed significantly reduced cytosolic calcium release in the fœtus amniocytes vs amniocytes from age-matched control fœtuses and in HeLa cells transfected with mutant ADGRL2 cDNA vs wild-type construct. Embryonic lethality was also observed in constitutive Adgrl2-/- mice. In Adgrl2+/- mice, MRI studies revealed microcephaly and vermis hypoplasia. Cell adhesion and wound healing assays demonstrated that the variation increased cell adhesion properties and reduced cell motility. Furthermore, HeLa cells overexpressing mutant ADGRL2 displayed a highly developed cytoplasmic F-actin network related to cytoskeletal dynamic modulation. ADGRL2 is the first gene identified as being responsible for extreme microcephaly with rhombencephalosynapsis. Increased cell adhesion, reduced cell motility and cytoskeletal dynamic alterations induced by the variant therefore represent a new mechanism responsible for microcephaly.

PMID: 30340542 [PubMed - in process]

Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction.

Neurol Genet. 2018 Oct;4(5):e276

Authors: Lee RG, Sedghi M, Salari M, Shearwood AJ, Stentenbach M, Kariminejad A, Goullee H, Rackham O, Laing NG, Tajsharghi H, Filipovska A

Abstract
Objective: Our goal was to identify the gene(s) associated with an early-onset form of Parkinson disease (PD) and the molecular defects associated with this mutation.
Methods: We combined whole-exome sequencing and functional genomics to identify the genes associated with early-onset PD. We used fluorescence microscopy, cell, and mitochondrial biology measurements to identify the molecular defects resulting from the identified mutation.
Results: Here, we report an association of a homozygous variant in CHCHD2, encoding coiled-coil-helix-coiled-coil-helix domain containing protein 2, a mitochondrial protein of unknown function, with an early-onset form of PD in a 26-year-old Caucasian woman. The CHCHD2 mutation in PD patient fibroblasts causes fragmentation of the mitochondrial reticular morphology and results in reduced oxidative phosphorylation at complex I and complex IV. Although patient cells could maintain a proton motive force, reactive oxygen species production was increased, which correlated with an increased metabolic rate.
Conclusions: Our findings implicate CHCHD2 in the pathogenesis of recessive early-onset PD, expanding the repertoire of mitochondrial proteins that play a direct role in this disease.

PMID: 30338296 [PubMed]

Molecular diagnosis of unexplained haemolytic anaemia using targeted next-generation sequencing panel revealed (p.Ala337Thr) novel mutation in GPI gene in two Indian patients.

J Clin Pathol. 2018 Oct 18;:

Authors: Kedar PS, Gupta V, Dongerdiye R, Chiddarwar A, Warang P, Madkaikar MR

Abstract
Glucose-6-phosphate isomerase (GPI) deficiency is an autosomal recessive genetic disorder causing congenital haemolytic anaemia (CHA). Diagnosis of GPI deficiency by the biochemical method is unpredicted. Molecular diagnosis by identifying genetic mutation is the gold standard method for confirmation of disease, but causative genes involved in CHA are numerous, and identifying a gene-by-gene approach using Sanger sequencing is also cumbersome, expensive and labour intensive. Recently, next-generation targeted sequencing is more useful in the diagnosis of unexplained haemolytic anaemia. We used targeted next-generation sequencing (NGS) clinical panel for diagnosis of unexplained haemolytic anaemia in two Indian patients which were pending for a long time. All possible causes of haemolytic anaemia were found within normal limit. NGS by clinical exome panel revealed homozygous novel missense mutation in exon 12, c.1009G>A (p.Ala337Thr) in both patients. We further confirm by measuring red blood cell GPI activity in the patients and showed deficiency whereas parents were having intermediate activity. c.1009G>A mutation was also confirmed by Sanger sequencing of exon 12 of GPI gene. The structural-functional analysis by bioinformatics software like Swiss PDB, PolyPhen-2 and PyMol suggested that this pathogenic variant has a direct impact on the structural rearrangement at the region near the active site of the enzyme. This rapid and high-performance targeted NGS assay can be configured to detect specific CHA mutations unique to an individual defect, making it a potentially valuable method for diagnosis of unexplained haemolytic anaemia.

PMID: 30337328 [PubMed - as supplied by publisher]

Neurotransmitter trafficking defect in a patient with clathrin (CLTC) variation presenting with intellectual disability and early-onset parkinsonism.

Parkinsonism Relat Disord. 2018 Oct 11;:

Authors: Manti F, Nardecchia F, Barresi S, Venditti M, Pizzi S, Hamdan FF, Blau N, Burlina A, Tartaglia M, Leuzzi V

Abstract
INTRODUCTION: Clathrins play a key role in endocytosis, recycling, and trafficking as well as the generation of presynaptic vesicles. We report a new clinical condition associated with a de novo variant in the CLTC gene, which encodes the clathrin heavy polypeptide.
CASE REPORT: This 30-year-old woman presented with a developmental disorder during childhood that progressed to mild cognitive decline in late childhood and relapsing-remitting hypokinetic-rigid syndrome with severe achalasia, weight loss, and mood disorder in adulthood. 123I-Ioflupane SPECT was normal. Blood phenylalanine was slightly increased and PAH sequencing revealed compound heterozygosity for two variants, p.[Asp151Glu]:[Thr380Met]. CSF examination unexpectedly detected a remarkable reduction of homovanillic, 5-hydroxyindolacetic, and 5-methylthetrahydrofolic acids, which could not be ascribed to any alteration of tetrahydrobiopterin and related biogenic amine pathways.
METHODS: Trio-based exome sequencing was performed.
RESULT: A de novo missense variant (c.2669C > T/p.Pro890Leu) was detected in CLTC. Treatment with biogenic amine precursors was ineffective, while the inhibitor of MAO-A selegiline resulted in persistent clinical improvement.
CONCLUSIONS: We suggest CLTC defect as a new disorder of biogenic amine trafficking, resulting in neurodevelopmental derangement and movement disorder. Neurotransmitter depletion in CSF may be a biomarker of this disease, and selegiline a possible treatment option.

PMID: 30337205 [PubMed - as supplied by publisher]

Evaluation of novel Parkinson's disease candidate genes in the Chinese population.

Neurobiol Aging. 2018 Sep 21;:

Authors: Chew EGY, Liany H, Tan LCS, Au WL, Prakash KM, Annuar AA, Chan AYY, Lim SY, Mok V, Chung SJ, Song K, Liu J, Foo JN, Tan EK

Abstract
Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese samples and genotyping coding variants in an independent set of 9756 Chinese samples. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean samples. We found that only 8 of 43 reported risk variants were polymorphic in our Chinese samples. We identified several heterozygotes for rare loss-of-function mutations, including the reported CD36 p.Gln74Ter variant, in both cases and controls. We also observed 2 potential compound heterozygotes among PD cases for rare loss-of-function mutations in CD36 and SSPO. The other reported variants were common in East Asians and not associated with PD, completely absent, or only found in controls. Therefore, the 33 reported candidate genes and associated variants are unlikely to confer significant PD risk in the East Asian population.

PMID: 30337193 [PubMed - as supplied by publisher]

Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers.

Neurobiol Aging. 2018 Sep 19;:

Authors: Fournier C, Barbier M, Camuzat A, Anquetil V, Lattante S, Clot F, Cazeneuve C, Rinaldi D, Couratier P, Deramecourt V, Sabatelli M, Belliard S, Vercelletto M, Forlani S, Jornea L, French Clinical and Genetic Research Network on FTLD/FTLD-ALS, PREVDEMALS and FTLD-Exome Study Groups, Leguern E, Brice A, Le Ber I

Abstract
A (GGGGCC)n repeat expansion in C9orf72 gene is the major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The relations between the repeats size and the age at disease onset (AO) or the clinical phenotype (FTD vs. ALS) were investigated in 125 FTD, ALS, and presymptomatic carriers. Positive correlations were found between repeats number and the AO (p < 10e-4) but our results suggested that the association was mainly driven by age at collection (p < 10e-4). A weaker association was observed with clinical presentation (p = 0.02), which became nonsignificant after adjustment for the age at collection in each group. Importantly, repeats number variably expanded or contracted over time in carriers with multiple blood samples, as well as through generations in parent-offspring pairs, conversely to what occurs in several expansion diseases with anticipation at the molecular level. Finally, this study establishes that measure of repeats number in lymphocytes is not a reliable biomarker predictive of the AO or disease outcome in C9orf72 long expansion carriers.

PMID: 30337192 [PubMed - as supplied by publisher]

Inflammatory Bowel Disease: What Very Early Onset Disease Teaches Us.

Gastroenterol Clin North Am. 2018 Dec;47(4):755-772

Authors: Crowley E, Muise A

Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, of which ulcerative colitis and Crohn's disease are the 2 most prevailing entities. Very early onset IBD (VEO-IBD) children diagnosed with IBD under age 6 years. Although the etiology of IBD is mostly unknown, it involves a complex interaction among host genetics, microbiota, environmental factors, and aberrant immune responses. Advances in the understanding of the genetic contribution, which appears to be much more significant in younger children, gives us a useful insight into the pathogenesis and potential future therapeutic targets in IBD.

PMID: 30337031 [PubMed - in process]

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation.

Nat Commun. 2018 Oct 17;9(1):4316

Authors: Ahlberg G, Refsgaard L, Lundegaard PR, Andreasen L, Ranthe MF, Linscheid N, Nielsen JB, Melbye M, Haunsø S, Sajadieh A, Camp L, Olesen SP, Rasmussen S, Lundby A, Ellinor PT, Holst AG, Svendsen JH, Olesen MS

Abstract
A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

PMID: 30333491 [PubMed - in process]

Molecular Genetics of Endometrial Carcinoma.

Annu Rev Pathol. 2018 Oct 17;:

Authors: Bell DW, Ellenson LH

Abstract
Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. Endometrioid endometrial carcinomas constitute approximately 85% of newly diagnosed cases; serous carcinomas represent approximately 3-10% of diagnoses; clear cell carcinoma accounts for <5% of diagnoses; and uterine carcinosarcomas are rare, biphasic tumors. Longstanding molecular observations implicate PTEN inactivation as a major driver of endometrioid carcinomas; TP53 inactivation as a major driver of most serous carcinomas, some high-grade endometrioid carcinomas, and many uterine carcinosarcomas; and inactivation of either gene as drivers of some clear cell carcinomas. In the past decade, targeted gene and exome sequencing have uncovered additional pathogenic aberrations in each histotype. Moreover, an integrated genomic analysis by The Cancer Genome Atlas (TCGA) resulted in the molecular classification of endometrioid and serous carcinomas into four distinct subgroups, POLE (ultramutated), microsatellite instability (hypermutated), copy number low (endometrioid), and copy number high (serous-like). In this review, we provide an overview of the major molecular features of the aforementioned histopathological subtypes and TCGA subgroups and discuss potential prognostic and therapeutic implications for endometrial carcinoma. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 30332563 [PubMed - as supplied by publisher]

A novel germline mutation in GP1BA gene N-terminal domain in monoallelic Bernard-Soulier syndrome.

Platelets. 2018 Oct 17;:1-7

Authors: Trizuljak J, Kozubík KS, Radová L, Pešová M, Pál K, Réblová K, Stehlíková O, Smejkal P, Zavřelová J, Pacejka M, Mayer J, Pospíšilová Š, Doubek M

Abstract
Mutations in the GP1BA gene have been associated with platelet-type von Willebrand disease and Bernard-Soulier syndrome. Here, we report a novel GP1BA mutation in a family with autosomal dominant macrothrombocytopenia and mild bleeding. We performed analyses of seven family members. Using whole-exome sequencing of germline DNA samples, we identified a heterozygous single-nucleotide change in GP1BA (exone2:c.176T>G), encoding a p.Leu59Arg substitution in the N-terminal domain, segregating with macrothrombocytopenia. This variant has not been previously reported. We also analysed the structure of the detected sequence variant in silico. In particular, we used the crystal structure of the human platelet receptor GP Ibα N-terminal domain. Replacement of aliphatic amino-acid Leu 59 with charged, polar and larger arginine probably disrupts the protein structure. An autosomal dominant mode of inheritance, a family history of mild bleeding episodes, aggregation pattern in affected individuals together with evidence of mutation occurring in part of the GP1BA gene encoding the leucine-rich repeat region suggest a novel variant causing monoallelic Bernard-Soulier syndrome.

PMID: 30332551 [PubMed - as supplied by publisher]

Unexpected ABCC6 mRNA splicing in a Chinese family with pseudoxanthoma elasticum.

Acta Ophthalmol. 2018 Oct 17;:

Authors: Sun Q, Wang W, Wu L, Cheng L, Tong X, Xu X

Abstract
PURPOSE: To identify the clinical characteristics and pathogenic genes among a Chinese family with angioid streaks and to assess a novel splicing mutation at the transcriptional and translational levels.
METHODS: Consenting family members were clinically evaluated, and blood samples were collected for targeted exome capture sequencing and/or Sanger sequencing. The two affected siblings were assessed by multimodal fundus imaging. ABCC6 splicing patterns were analysed by RNA identification and quantification using the proband's peripheral blood mononuclear cells. Minigene experiments were performed to verify the university. Plasmids expressing the transcripts were transfected into HEK293 cells to assess protein translation. Bioinformatic analyses were also performed to predict the splicing patterns and the functional consequences of the mutation.
RESULTS: The two siblings were trans-compound heterozygous pseudoxanthoma elasticum (PXE) patients with the same genotype (c.3703C>T and c.1177-2A>G for ABCC6) but different phenotypes. We identified several ABCC6 alternative splicing transcripts that were not previously reported. The novel splicing mutation c.1177-2A>G led to the upregulation of three transcripts, one using a cryptic splice acceptor in the upstream region of the intron, another using a cryptic splice acceptor in the downstream exon, and the third stimulating non-canonical U12-type splicing. All the transcripts were successfully translated in vitro.
CONCLUSION: The genotype-phenotype correlation of PXE is poorly understood. The novel ABCC6 splicing mutation c.1177-2A>G results in multiple splicing patterns. Endogenous U2 to U12 conversion may occur in humans in a disease state. Peripheral blood mononuclear cells can be reliably used to study ABCC6 RNA.

PMID: 30328268 [PubMed - as supplied by publisher]

Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

J Med Genet. 2018 Oct 16;:

Authors: Shalata A, Lauhasurayotin S, Leibovitz Z, Li H, Hebert D, Dhanraj S, Hadid Y, Mahroum M, Bajar J, Egenburg S, Arad A, Shohat M, Haddad S, Bakry H, Moshiri H, Scherer SS, Tzur S, Dror Y

Abstract
BACKGROUND: Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown.
OBJECTIVE: To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families.
METHODS: Medical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype.
RESULTS: We report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure.
CONCLUSION: We propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.

PMID: 30327448 [PubMed - as supplied by publisher]

Wide phenotypic spectrum in axonal Charcot-Marie-Tooth neuropathy type 2 patients with KIF5A mutations.

Genes Genomics. 2018 01;40(1):77-84

Authors: Nam DE, Yoo DH, Choi SS, Choi BO, Chung KW

Abstract
The kinesin heavy chain isoform 5A (KIF5A) gene, which encodes a microtubule-based motor protein, plays an important role in the transport of organelles in the nerve cells. Mutations in the KIF5A showed a wide phenotypic spectrum from hereditary spastic paraplegia (HSP) to axonal Charcot-Marie-Tooth peripheral neuropathy type 2 (CMT2). This study identified three pathogenic KIF5A mutations in Korean CMT2 patients by whole exome sequencing. Two mutations (p.Arg204Trp and p.Arg280His) were previously reported, but p.Leu558Pro was determined to be a novel de novo mutation. All the mutations were not observed in the healthy controls and were located in highly conserved domains among vertebrate species. The p.Arg204Trp mutation was identified from a CMT2 patient with additional complex phenotypes of HSP, ataxia, fatigability and pyramidal sign, but the p.Arg280His and p.Leu588Pro mutations were identified in each axonal CMT2 patient. The p.Arg204Trp mutation was previously reported in a HSP patient with no CMT symptom. The p.Arg280His mutation was reported in a CMT2 patient, which was similarly with our case. However, it was also once reported in a HSP patient with pes cavus. As the first report in Korea, this study identified three KIF5A mutations as the underlying cause of axonal peripheral neuropathy with or without the HSP phenotype. We confirmed a wide inter- and intra-allelic phenotypic spectrum by the mutations in the KIF5A.

PMID: 29892902 [PubMed - in process]

ProxECAT: Proxy External Controls Association Test. A new case-control gene region association test using allele frequencies from public controls.

PLoS Genet. 2018 Oct;14(10):e1007591

Authors: Hendricks AE, Billups SC, Pike HNC, Farooqi IS, Zeggini E, Santorico SA, Barroso I, Dupuis J

Abstract
A primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous total number of sequenced genomes, individual studies of complex traits and diseases are often smaller and underpowered to detect rare variant genetic associations. Existing genetic resources such as the Exome Aggregation Consortium (>60,000 exomes) and the Genome Aggregation Database (~140,000 sequenced samples) have the potential to be used as controls in these studies. Fully utilizing these and other existing sequencing resources may increase power and could be especially useful in studies where resources to sequence additional samples are limited. However, to date, these large, publicly available genetic resources remain underutilized, or even misused, in large part due to the lack of statistical methods that can appropriately use this summary level data. Here, we present a new method to incorporate external controls in case-control analysis called ProxECAT (Proxy External Controls Association Test). ProxECAT estimates enrichment of rare variants within a gene region using internally sequenced cases and external controls. We evaluated ProxECAT in simulations and empirical analyses of obesity cases using both low-depth of coverage (7x) whole-genome sequenced controls and ExAC as controls. We find that ProxECAT maintains the expected type I error rate with increased power as the number of external controls increases. With an accompanying R package, ProxECAT enables the use of publicly available allele frequencies as external controls in case-control analysis.

PMID: 30325923 [PubMed - in process]