Family-based exome-wide association study of childhood acute lymphoblastic leukemia among Hispanics confirms role of ARID5B in susceptibility.

PLoS One. 2017;12(8):e0180488

Authors: Archer NP, Perez-Andreu V, Stoltze U, Scheurer ME, Wilkinson AV, Lin TN, Qian M, Goodings C, Swartz MD, Ranjit N, Rabin KR, Peckham-Gregory EC, Plon SE, de Alarcon PA, Zabriskie RC, Antillon-Klussmann F, Najera CR, Yang JJ, Lupo PJ

Abstract
We conducted an exome-wide association study of childhood acute lymphoblastic leukemia (ALL) among Hispanics to confirm and identify novel variants associated with disease risk in this population. We used a case-parent trio study design; unlike more commonly used case-control studies, this study design is ideal for avoiding issues with population stratification bias among this at-risk ethnic group. Using 710 individuals from 323 Guatemalan and US Hispanic families, two inherited SNPs in ARID5B reached genome-wide level significance: rs10821936, RR = 2.31, 95% CI = 1.70-3.14, p = 1.7×10-8 and rs7089424, RR = 2.22, 95% CI = 1.64-3.01, p = 5.2×10-8. Similar results were observed when restricting our analyses to those with the B-ALL subtype: ARID5B rs10821936 RR = 2.22, 95% CI = 1.63-3.02, p = 9.63×10-8 and ARID5B rs7089424 RR = 2.13, 95% CI = 1.57-2.88, p = 2.81×10-7. Notably, effect sizes observed for rs7089424 and rs10821936 in our study were >20% higher than those reported among non-Hispanic white populations in previous genetic association studies. Our results confirmed the role of ARID5B in childhood ALL susceptibility among Hispanics; however, our assessment did not reveal any strong novel inherited genetic risks for acute lymphoblastic leukemia among this ethnic group.

PMID: 28817678 [PubMed - in process]

Prenatal presentation of Mabry syndrome with congenital diaphragmatic hernia and phenotypic overlap with Fryns syndrome.

Am J Med Genet A. 2017 Aug 17;:

Authors: Reynolds KK, Juusola J, Rice GM, Giampietro PF

Abstract
We report on a family in which initial features were compatible with Fryns syndrome. The first sibling was a stillborn female with a left diaphragmatic hernia (DH). Her clinical features overlapped with Fryns syndrome. The second pregnancy, a male fetus, was followed for polyhydramnios, hypoplastic mandible, mild enlargement of the fetal bladder, hydronephrosis, and rocker bottom foot deformities. He had facial features similar to his sibling and a large cleft of the secondary palate, small jaw, and secundum atrial septal defect. He underwent surgical repair of imperforate anus, intestinal malrotation, and placement of mucous fistula for biopsy positive Hirschsprung disease. An elevated alkaline phosphatase level of 1569 U/L was reported. Whole exome sequencing performed on the second child demonstrated compound heterozygosity for the PIGV gene with the p.A341E and p.A418D variants in trans. Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by mutations in PIGV and includes hyperphosphatasia as a diagnostic hallmark. Our patient exhibited hyperphosphatasia but without any storage material in his skin cells. His features remain similar to his sister's, but includes seizures and lacks diaphragmatic hernia. Until now, HPMRS and Fryns syndrome, despite overlapping features, were considered mutually exclusive as HPMRS involves hyperphosphatasia and Fryns typically exhibits DH. Recent identification of PIGN mutations associated with several cases of Fryns syndrome point to a common pathogenetic etiology involving inborn errors of the glycosylphosphatidylinositiol anchor biosynthetic pathway. A diagnosis of HPMRS should be considered when DH is encountered on prenatal ultrasound.

PMID: 28817240 [PubMed - as supplied by publisher]

Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression.

Hum Mol Genet. 2016 May 01;25(9):1836-45

Authors: Smith J, Read ML, Hoffman J, Brown R, Bradshaw B, Campbell C, Cole T, Navas JD, Eatock F, Gundara JS, Lian E, Mcmullan D, Morgan NV, Mulligan L, Morrison PJ, Robledo M, Simpson MA, Smith VE, Stewart S, Trembath RC, Sidhu S, Togneri FS, Wake NC, Wallis Y, Watkinson JC, Maher ER, McCabe CJ, Woodward ER

Abstract
Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-encoded ERβ expression in the MTC tumour. ERα and ERβ form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERβ represses ERα-mediated activation of the ERE and the RET promoter contains three EREs. In vitro, we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo, immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.

PMID: 26945007 [PubMed - indexed for MEDLINE]

Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

J Dent Res. 2017 Aug 01;:22034517724149

Authors: Dinckan N, Du R, Petty LE, Coban-Akdemir Z, Jhangiani SN, Paine I, Baugh EH, Erdem AP, Kayserili H, Doddapaneni H, Hu J, Muzny DM, Boerwinkle E, Gibbs RA, Lupski JR, Uyguner ZO, Below JE, Letra A

Abstract
Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

PMID: 28813618 [PubMed - as supplied by publisher]

Leveraging network analytics to infer patient syndrome and identify causal genes in rare disease cases.

BMC Genomics. 2017 Aug 11;18(Suppl 5):551

Authors: Krämer A, Shah S, Rebres RA, Tang S, Richards DR

Abstract
BACKGROUND: Next-generation sequencing is widely used to identify disease-causing variants in patients with rare genetic disorders. Identifying those variants from whole-genome or exome data can be both scientifically challenging and time consuming. A significant amount of time is spent on variant annotation, and interpretation. Fully or partly automated solutions are therefore needed to streamline and scale this process.
RESULTS: We describe Phenotype Driven Ranking (PDR), an algorithm integrated into Ingenuity Variant Analysis, that uses observed patient phenotypes to prioritize diseases and genes in order to expedite causal-variant discovery. Our method is based on a network of phenotype-disease-gene relationships derived from the QIAGEN Knowledge Base, which allows for efficient computational association of phenotypes to implicated diseases, and also enables scoring and ranking.
CONCLUSIONS: We have demonstrated the utility and performance of PDR by applying it to a number of clinical rare-disease cases, where the true causal gene was known beforehand. It is also shown that PDR compares favorably to a representative alternative tool.

PMID: 28812537 [PubMed - in process]

Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene.

Pediatr Dev Pathol. 2017 Sep-Oct;20(5):416-420

Authors: Martín-Hernández E, García-Silva MT, Quijada-Fraile P, Rodríguez-García ME, Rivera H, Hernández-Laín A, Coca-Robinot D, Fernández-Toral J, Arenas J, Martín MA, Martínez-Azorín F

Abstract
Whole-exome sequencing was used to identify the disease gene(s) in a Spanish girl with failure to thrive, muscle weakness, mild facial weakness, elevated creatine kinase, deficiency of mitochondrial complex III and depletion of mtDNA. With whole-exome sequencing data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The analysis of whole exome uncovered a homozygous pathogenic mutation in thymidine kinase 2 gene ( TK2; NM_004614.4:c.323 C>T, p.T108M). TK2 mutations have been identified mainly in patients with the myopathic form of mtDNA depletion syndromes. This patient presents an atypical TK2-related myopathic form of mtDNA depletion syndromes, because despite having a very low content of mtDNA (<20%), she presents a slower and less severe evolution of the disease. In conclusion, our data confirm the role of TK2 gene in mtDNA depletion syndromes and expanded the phenotypic spectrum.

PMID: 28812460 [PubMed - in process]

Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease.

Neurol Genet. 2017 Oct;3(5):e177

Authors: Ruiz-Martínez J, Azcona LJ, Bergareche A, Martí-Massó JF, Paisán-Ruiz C

Abstract
OBJECTIVE: Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.
METHODS: In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.
RESULTS: Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.
CONCLUSIONS: We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

PMID: 28808687 [PubMed]

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.

Proc Natl Acad Sci U S A. 2017 Aug 14;:

Authors: Timberlake AT, Furey CG, Choi J, Nelson-Williams C, Yale Center for Genome Analysis, Loring E, Galm A, Kahle KT, Steinbacher DM, Larysz D, Persing JA, Lifton RP

Abstract
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10(-11)). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

PMID: 28808027 [PubMed - as supplied by publisher]

Diagnostic exome sequencing identifies a heterozygous MBD5 frameshift mutation in a family with intellectual disability and epilepsy.

Eur J Med Genet. 2017 Aug 11;:

Authors: Han JY, Lee IG, Jang W, Kim M, Kim Y, Jang JH, Park J

Abstract
Methyl-CpG-binding domain 5 (MBD5)-associated neurodevelopmental disorder caused by 2q23.1 or MBD5-specific mutation has been recently identified as a genetic disorder associated with autism spectrum disorders. Phenotypic features of 2q23.1 deletion or disruption of MBD5 gene include severe intellectual disability, seizure, significant speech impairment, sleep disturbance, and autistic-like behavioural problems. Here we report a 7-year-old girl with intellectual disability and epilepsy without previous clinical diagnosis. Diagnostic exome sequencing identified a novel frameshift mutation c.254_255delGA (p.Arg85Asnfs*6) in the MBD5 gene of the proband and her father. The proband's father with normal intelligence showed subclinical manifestations observed in subsequent investigations. Clinical manifestations, disease course, and molecular findings of the involvement of MBD5 gene in this family suggest an unusual MBD5-related neurodevelopmental disorder. Moreover, this report demonstrates the critical role of next-generation sequencing technique in characterizing such a rare disorder with variable or no clinical manifestation and providing opportunity to develop effective preventive measures such as pre-implantation genetic diagnosis.

PMID: 28807762 [PubMed - as supplied by publisher]

Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.

Genome Med. 2017 Aug 14;9(1):73

Authors: Bostwick BL, McLean S, Posey JE, Streff HE, Gripp KW, Blesson A, Powell-Hamilton N, Tusi J, Stevenson DA, Farrelly E, Hudgins L, Yang Y, Xia F, Wang X, Liu P, Walkiewicz M, McGuire M, Grange DK, Andrews MV, Hummel M, Madan-Khetarpal S, Infante E, Coban-Akdemir Z, Miszalski-Jamka K, Jefferies JL, Members of the Undiagnosed Diseases Network, Rosenfeld JA, Emrick L, Nugent KM, Lupski JR, Belmont JW, Lee B, Lalani SR

Abstract
BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.
METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.
RESULTS: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.
CONCLUSIONS: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

PMID: 28807008 [PubMed - in process]

Loss of the chromatin modifier Kdm2aa causes BrafV600E-independent spontaneous melanoma in zebrafish.

PLoS Genet. 2017 Aug 14;13(8):e1006959

Authors: Scahill CM, Digby Z, Sealy IM, Wojciechowska S, White RJ, Collins JE, Stemple DL, Bartke T, Mathers ME, Patton EE, Busch-Nentwich EM

Abstract
KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease. Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequency. Fish homozygous for two independent premature stop codon alleles show reduced growth and survival, a strong male sex bias, and homozygous females exhibit a progressive oogenesis defect. kdm2aa mutant fish also develop melanomas from early adulthood onwards which are independent from mutations in braf and other common oncogenes and tumour suppressors as revealed by deep whole exome sequencing. In addition to effects on translation and DNA replication gene expression, high-replicate RNA-seq in morphologically normal individuals demonstrates a stable regulatory response of epigenetic modifiers and the specific de-repression of a group of zinc finger genes residing in constitutive heterochromatin. Together our data reveal a complex role for Kdm2aa in regulating normal mRNA levels and carcinogenesis. These findings establish kdm2aa mutants as the first single gene knockout model of melanoma biology.

PMID: 28806732 [PubMed - as supplied by publisher]

Novel clinical manifestations in patients with KCNA2 mutations.

Seizure. 2017 Aug 05;51:74-76

Authors: Sachdev M, Gaínza-Lein M, Tchapyjnikov D, Jiang YH, Loddenkemper T, Mikati MA

Abstract
PURPOSE: To report novel clinical manifestations of KCNA2 mutation related epileptic encephalopathy.
METHODS: Blood samples were sent for whole exome and Sanger sequencing. Seizure types were characterized by clinical criteria and EEG recording.
RESULTS: KCNA2 mutations have been reported in 10 cases who presented with focal, absence, generalized tonic-clonic or myoclonic astatic seizures. Here we describe 3 patients with previously unreported, more severe manifestations. Patient 1 is a 5 year-old male with a c.1214 C > T (p.Pro405Leu) mutation, previously reported to be disease causing. He presented at 1year of age with focal seizures and subsequently developed electrical status epilepticus of sleep at age 3. The latter finding to our knowledge has never been reported in patients with KCNA2 mutations. Patient 2 is a 7 year-old female with a novel c.1195 G > A (p.Val399Met) mutation not previously described. She presented with intermittent then continuous polymyoclonus and myoclonic-astatic and generalized tonic clonic seizures. Continuous polymyoclonus is another new manifestation in patients with KCNA2 mutations. Patient 3 is a 23 year-old male with a c.889C > T (p.Arg297Trp) mutation not previously described. He presented at 4 years of age with generalized tonic clonic seizures and later developed recurrent refractory status epilepticus episodes at ages 19, 22 and 23 years, the latter being a novel manifestation in patients with KCNA2 mutations.
CONCLUSION: We identified 3 patients with KCNA2 mutations with novel characteristics, including electrical status epilepticus of sleep, continuous polymyoclonus and status epilepticus. These results expand KCNA2 mutation epileptic manifestations to include more severe, previously unreported phenotypes.

PMID: 28806589 [PubMed - as supplied by publisher]

Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population.

Andrology. 2017 Aug 14;:

Authors: Yang B, Wang J, Zhang W, Pan H, Li T, Liu B, Li H, Wang B

Abstract
Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) mutations are the main pathogenic cause, although a proportion of cases are still unexplained. Recently, adhesion G protein-coupled receptor G2 (ADGRG2) gene, a novel pathogenic gene for CBAVD was identified. We did a single population replication study in Chinese CBAVD patients to replicate its role in CBAVD developing. In this study, we performed whole-exome sequencing in 18 unrelated CBAVD patients and identified two missense variants in two patients (c.G1709A, p.C570Y; and c.A2968G, p.K990E). Both variants were predicted to be deleterious and highly conserved in silico. The p.C570Y variant is located in the G protein-coupled receptor (GPCR) proteolysis site domain, which is functionally necessary for autoproteolysis, while the p.K990E variant is in the N-terminal fragment that may regulate activity of the adhesion GPCR. We did not find any potential pathogenic CFTR variants, implying the ADGRG2 variants are the genetic cause in these patients. To the best of our knowledge, these are the first two ADGRG2 variants to be identified in Chinese CBAVD patients, which further validate the disease-causing role of ADGRG2 in this congenital defect.

PMID: 28805948 [PubMed - as supplied by publisher]

Lack of FOXE3 coding mutation in a case of congenital aphakia.

Ophthalmic Genet. 2017 Aug 14;:1-4

Authors: Sano Y, Matsukane Y, Watanabe A, Sonoda KH, Kondo H

Abstract
PURPOSE: To report the findings in a patient with congenital primary aphakia, a rare disease known to be caused by mutations in the FOXE3 gene.
METHODS: The clinical appearances and visual functions of the patient were determined from the medical records. Genetic analyses were performed to search for mutations in the FOXE3 gene by Sanger sequencing and whole exome sequencing.
RESULTS: The 2-month-old male patient first presented with bilateral congenital aphakia associated with microphthalmia, corneal opacity, and dysplasia of the anterior segment. At the age of 2-years, his visual acuity in the left eye was 20/1000 at 30 cm, he was able to discriminate red, blue, and yellow light stimuli, and a b-wave was recorded by scotopic combined rod-cone electroretinograms. The right eye became blind during the follow-up period. No mutation in the FOXE3 gene was detected.
CONCLUSION: Although congenital aphakia is known to be caused by mutations in the FOXE3 gene, the results of lack of coding mutation in this patient suggests a possible genetic heterogeneity of the disease.

PMID: 28805541 [PubMed - as supplied by publisher]

Settling the score: variant prioritization and Mendelian disease.

Nat Rev Genet. 2017 Aug 14;:

Authors: Eilbeck K, Quinlan A, Yandell M

Abstract
When investigating Mendelian disease using exome or genome sequencing, distinguishing disease-causing genetic variants from the multitude of candidate variants is a complex, multidimensional task. Many prioritization tools and online interpretation resources exist, and professional organizations have offered clinical guidelines for review and return of prioritization results. In this Review, we describe the strengths and weaknesses of widely used computational approaches, explain their roles in the diagnostic and discovery process and discuss how they can inform (and misinform) expert reviewers. We place variant prioritization in the wider context of gene prioritization, burden testing and genotype-phenotype association, and we discuss opportunities and challenges introduced by whole-genome sequencing.

PMID: 28804138 [PubMed - as supplied by publisher]

Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family.

Int J Pediatr Otorhinolaryngol. 2017 Sep;100:1-7

Authors: Niu Z, Feng Y, Hu Z, Li J, Sun J, Chen H, He C, Wang X, Jiang L, Liu Y, Cai X, Wang L, Cai Y, Liu X, Mei L

Abstract
OBJECTIVE: Autosomal dominant non-syndromic low-frequency sensorineural hearing loss (LFSNHL) DFNA6/14/38 is an uncommon type of hearing loss that classically affects low frequencies of 2000 Hz and below, demonstrating an ascending configuration. The current study aimed to investigate the cause of LFSNHL in a five-generation Chinese family.
METHODS: The phenotype of the Chinese family was characterized using audiologic testing and pedigree analysis. The combined approach of array screening and whole-exome sequencing was used to identify the disease-causing gene in this family.
RESULTS: This pedigree, in which the affected subjects presented isolated low-frequency sensorineural hearing impairment with childhood onset, was associated with autosomal dominant inheritance of the c.2591A > G mutation in exon 8 of the Wolframin syndrome 1 (WFS1) gene which was not present in 286 unrelated controls with matched ancestry and is highly conserved across species. In addition, several mutations affecting the Glu864 residue have been previously identified in different populations, suggesting that this site is likely to be a mutational hot spot.
CONCLUSIONS: We identified a novel substitution, Glu864Gly, of WFS1 as the causative variant for this pedigree. Our data extend the mutation spectrum of the WFS1 gene in Chinese individuals and may contribute to establishing a better genotype-phenotype correlation for LFSNHL.

PMID: 28802351 [PubMed - in process]

Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

Metabolism. 2017 Jun;71:213-225

Authors: Elouej S, Beleza-Meireles A, Caswell R, Colclough K, Ellard S, Desvignes JP, Béroud C, Lévy N, Mohammed S, De Sandre-Giovannoli A

Abstract
BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition.
PATIENTS AND METHODS: We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents.
RESULTS: Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing of POLD1 exon 15 revealed the recurrent in-frame deletion (c.1812_1814del, p.S605del).
CONCLUSION: Our work highlights that mutations in different POLD1 domains can lead to phenotypic variability, ranging from dominantly inherited cancer predisposition syndromes, to mild MDPL phenotypes without lifespan reduction, to very severe MDPL syndromes with major premature aging features. These results also suggest that POLD1 gene testing should be considered in patients presenting with severe progeroid features.

PMID: 28521875 [PubMed - indexed for MEDLINE]

Exome Array Analysis Identifies Variants in SPOCD1 and BTN3A2 That Affect Risk for Gastric Cancer.

Gastroenterology. 2017 Jun;152(8):2011-2021

Authors: Zhu M, Yan C, Ren C, Huang X, Zhu X, Gu H, Wang M, Wang S, Gao Y, Ji Y, Miao X, Yang M, Chen J, Du J, Huang T, Jiang Y, Dai J, Ma H, Zhou J, Wang Z, Hu Z, Ji G, Zhang Z, Shen H, Shi Y, Jin G

Abstract
BACKGROUND & AIMS: Several genetic variants have been associated with gastric cancer risk, although these account for only a fraction of cases of gastric cancer. We aimed to identify low-frequency and other genetic variants that determine gastric cancer susceptibility.
METHODS: We performed exome array analysis of DNA in blood samples from 1113 patients with gastric cancer, collected at hospitals from 2006 to 2010 in China, and 1848 individuals without cancer (controls) undergoing physical examinations. Among 71,290 variants analyzed (including 25,784 common variants), 24 variants were selected and replicated in an analysis of DNA in blood samples from 4687 additional cases of gastric cancer and 5780 controls. We compared expression of candidate genes in tumor vs normal gastric tissues using data from TCGA and performed functional annotation analyses. An immortalized human gastric epithelial cell line (GES1) and 7 human gastric cancer lines were used to express transgenes, knock down gene expression (with small interfering RNAs), disrupt genes (using the CRISPR/Cas9 system), or assess expression of reporter constructs. We measured cell proliferation, colony formation, invasion, and migration, and assessed growth of xenograft tumors in nude mice.
RESULTS: A low-frequency missense variant rs112754928 in the SPOC domain containing 1 gene (SPOCD1; encoding p.Arg71Trp), at 1p35.2, was reproducibly associated with reduced risk of gastric cancer (odds ratio, 0.56; P = 3.48 × 10(-8)). SPOCD1 was overexpressed in gastric tumors, and knockout of SPOCD1 reduced gastric cancer cell proliferation, invasive activity, and migration, as well as growth of xenograft tumors in nude mice. We also associated the variant rs1679709 at 6p22.1 with reduced risk for gastric cancer (odds ratio, 0.80; P = 1.17 × 10(-13)). The protective allele rs1679709-A correlated with the surrounding haplotype rs2799077-T-rs2799079-C, which reduced the enhancer activity of this site to decrease expression of the butyrophilin subfamily 3 member A2 gene (BTN3A2). BTN3A2 is overexpressed in gastric tumors, and deletion of BTN3A2 inhibited proliferation, migration, and invasion of gastric cancer cells.
CONCLUSIONS: We have associated variants at 1p35.2 and 6p22.1 with gastric cancer risk, indicating a role for SPOCD1 and BTN3A2 in gastric carcinogenesis.

PMID: 28246015 [PubMed - indexed for MEDLINE]

Epileptic Encephalopathies-Clinical Syndromes and Pathophysiological Concepts.

Curr Neurol Neurosci Rep. 2017 Feb;17(2):10

Authors: von Deimling M, Helbig I, Marsh ED

Abstract
Epileptic encephalopathies account for a large proportion of the intractable early-onset epilepsies and are characterized by frequent seizures and poor developmental outcome. The epileptic encephalopathies can be loosely divided into two related groups of named syndromes. The first comprises epilepsies where continuous EEG changes directly result in cognitive and developmental dysfunction. The second includes patients where cognitive impairment is present at seizure onset and is due to the underlying etiology but the epileptic activity may then worsen the cognitive abilities over time. Recent, large-scale exome studies have begun to establish the genetic architecture of the epileptic encephalopathies, resulting in a re-consideration of the boundaries of these named syndromes. The emergence of this genetic architecture has lead to three main pathophysiological concepts to provide a mechanistic framework for these disorders. In this article, we will review the classic syndromes, the most significant genetic findings, and relate both to the pathophysiological understanding of epileptic encephalopathies.

PMID: 28229394 [PubMed - indexed for MEDLINE]

An effective combination of whole-exome sequencing and runs of homozygosity for the diagnosis of primary ciliary dyskinesia in consanguineous families.

Sci Rep. 2017 Aug 11;7(1):7905

Authors: Guo T, Tan ZP, Chen HM, Zheng DY, Liu L, Huang XG, Chen P, Luo H, Yang YF

Abstract
Primary ciliary dyskinesia (PCD) is clinically characterized by neonatal respiratory distress, chronic sinusitis, bronchiectasis and infertility, and situs inversus in 50% of the patients. PCD is a result of mutations in genes encoding proteins involved in ciliary function, and is primarily inherited in an autosomal recessive fashion. Diagnosis of PCD is often a challenging task due to its high clinical and genetic heterogeneities. In the present study, we attempted to use whole-exome sequencing (WES) combined with runs of homozygosity (ROH) approaches to identify the genetic defects in four Chinese consanguineous families with clinical PCD. We successfully identified three recently acknowledged PCD genes: DYX1C1, CCNO and ARMC4, and one well-characterized PCD gene, DNAI1. Our study provides compelling evidence that WES in combination with ROH analysis is an efficient diagnostic tool for identifying genetic causes of PCD in consanguineous families. Furthermore, our work expands the genetic mutation spectrum in PCD, and provides the additional tools to better serve the counseling of the families with PCD.

PMID: 28801648 [PubMed - in process]