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A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the ER quality control in the mechanism of some β3GalT6-pathy mutations.
We report a disease-causing variant c.618C>G, p.(Cys206Trp) in one patient originally described as Al-Gazali syndrome and reported in 1999. We evaluated the involvement of the Endoplasmic-reticulum-associated protein degradation (ERAD), in the pathogenesis of thirteen B3GALT6 variants. Retention in ER was evident in six of them while the c.618C>G, p.(Cys206Trp) and the other six variants trafficked normally. Our findings confirm the involvement of B3GALT6 in the pathogenesis of Al-Gazali syndrome and suggest that Al-Gazali syndrome represents the severe end of the spectrum of the phenotypes caused by pathogenic varia...
Source: Clinical Genetics - February 14, 2018 Category: Genetics & Stem Cells Authors: Ben-Mahmoud A, Ben-Salem S, Al-Sorkhy M, John A, Ali BR, Al-Gazali L Tags: Clin Genet Source Type: research

Exome sequencing reveals three homozygous missense variants in SNRPA in two sisters with syndromic intellectual disability.
We describe the previously unreported concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in two female siblings with three homozygous missense variants in SNRPA (a component of the U1 small nuclear ribonucleoprotein complex) characterized by homozygosity mapping and whole exome sequencing. Combined, c.97A>G, c.98T>C, and c.100T>A, in exon 2 of SNRPA lead to p.Ile33Ala and p.Phe34Ile exchanges, which were predicted in silico to be deleterious. Although both patients exhibited some clinical features seen in other spliceosomal disorders, their complete clinic...
Source: Clinical Genetics - February 13, 2018 Category: Genetics & Stem Cells Authors: Rangel-Sosa MM, Figuera-Villanueva LE, González-Ramos IA, Pérez-Páramo YX, Martínez-Jacobo LA, Arnaud-López L, Nastasi-Catanese JA, Rivas-Estilla AM, Galán-Huerta KA, Rojas-Martínez A, Ortiz-López R, Córdova-Fletes C Tags: Clin Genet Source Type: research

Cancer gene-panel testing identifies two loss-of-function alleles in PALB2 and PTEN.
Abstract Synchronous loss-of-function mutations in the cancer predisposing genes, PTEN and PALB2 identified by multigene panel. PMID: 29430632 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 11, 2018 Category: Genetics & Stem Cells Authors: Avgerinou C, Fostira F, Economopoulou P, Psyrri A Tags: Clin Genet Source Type: research

Characteristics of genetic diseases in consanguineous populations in the genomic era: lessons from Arab communities in North Israel.
Abstract The health outcome of consanguineous/endogamous unions is an increased risk of autosomal recessive disorders in their progeny. This manuscript is focused on consanguineous/endogamous populations living in North Israel. Molecular tools show that spouses' relatedness and hence their risks for congenital diseases among offspring are often greater than the risk calculated on the basis of reported pedigrees. Revealing founder mutations allows for effective genetic counseling, but also induces genetic screening of the whole community in case the mutations are found to be frequent. More complex genetic mechanism...
Source: Clinical Genetics - February 10, 2018 Category: Genetics & Stem Cells Authors: Shalev SA Tags: Clin Genet Source Type: research

Intrafamiliar clinical variability of Circumferential Skin Creases Kunze Type caused by a novel heterozygous mutation of N-terminal TUBB gene.
We report a 9-year-old boy with a diagnosis of CSC-KT based on MTBS, facial dysmorphism, microcephaly, severe ID, cortical atrophy and corpus callosum hypoplasia. Sanger sequencing identified a novel heterozygous c.218T>C (p.Met73Thr) mutation in the N-terminal of TUBB gene, that was inherited from the mother affected by isolated MTBS. This is the first report of inherited TUBB gene-related CSC-KT resulting from a novel heterozygous mutation in the N-terminal domain. Present data support the role of TUBB mutations in CSC-KT and definitely includes CSC-KT syndrome within the tubulinopathies. PMID: 29427453 [PubMed -...
Source: Clinical Genetics - February 10, 2018 Category: Genetics & Stem Cells Authors: Dentici ML, Terracciano A, Bellacchio E, Capolino R, Novelli A, Digilio MC, Dallapiccola B Tags: Clin Genet Source Type: research

Identification of a novel lethal form of autosomal recessive ichthyosis caused by UDP-glucose ceramide glucosyltransferase deficiency.
PMID: 29417556 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Monies D, Anabrees J, Ibrahim N, Elbardisy H, Abouelhoda M, Meyer BF, Alkuraya FS Tags: Clin Genet Source Type: research

Rare, genetically conditioned forms of rickets - differential diagnosis and advances in diagnostics and treatment.
Abstract Apart from the classic forms of rickets, there are rare genetic disorders from the group of vitamin D-resistant rickets where the clinical picture is very similar to the classic forms. Diagnosis of genetically conditioned rickets is often delayed. It is very important to know that a disorder of genetic background may be the cause of the failure of classic treatment in patients with rachitic symptoms. In the group of genetically conditioned rickets there are, among others, congenital hypophosphatemic rickets and vitamin D-dependent rickets type I and II. Congenital hypophosphatemic rickets is characterised...
Source: Clinical Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Michałus I, Rusińska A Tags: Clin Genet Source Type: research

Genetic and Clinical Findings in a Chinese Cohort of Patients with collagen VI-Related Myopathies.
Abstract Collagen VI-related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with forty UCMD and twenty BM. Muscle with biopsies revealed dystrophic changes and...
Source: Clinical Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Fan Y, Liu A, Wei C, Yang H, Chang X, Wang S, Yuan Y, Bonnemann C, Wu Q, Wu X, Xiong H Tags: Clin Genet Source Type: research

Phenotypic Characterization of KCTD3-related Developmental Epileptic Encephalopathy.
In this report, we describe the clinical phenotype associated with two pathogenic variants in KCTD3 gene. Seven individuals (including one set of monozygotic twin) from four consanguineous families presented with developmental epileptic encephalopathy, global developmental delay, central hypotonia, progressive peripheral hypertonia, and variable dysmorphic facial features. Posterior fossa abnormalities (ranging from Dandy-Walker malformation to isolated hypoplasia of the cerebellar vermis) were consistently observed in addition to other variable neuroradiological abnormalities such as hydrocephalus and abnormal brain myeli...
Source: Clinical Genetics - February 6, 2018 Category: Genetics & Stem Cells Authors: Faqeih EA, Almannai M, Saleh MM, AlWadie AH, Samman MM, Alkuraya FS Tags: Clin Genet Source Type: research

Prenatal detection of uniparental disomy of chromosome 2 carrying a CHRND pathogenic variant that causes lethal multiple pterygium syndrome.
PMID: 29399782 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 5, 2018 Category: Genetics & Stem Cells Authors: Shen W, Young BA, Bosworth M, Wright KE, Lamb AN, Ji Y Tags: Clin Genet Source Type: research

Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome.
Abstract Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K+ and Ca2+ and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep ...
Source: Clinical Genetics - February 5, 2018 Category: Genetics & Stem Cells Authors: Angius A, Cossu S, Uva P, Oppo M, Onano S, Persico I, Fotia G, Atzeni R, Cuccuru G, Asunis M, Cucca F, Pruna D, Crisponi L Tags: Clin Genet Source Type: research

SAAMP 2.0: an algorithm to predict genotype-phenotype correlation of lysosomal storage diseases.
Abstract Lysosomal storage diseases (LSDs) are a group of genetic disorders, resulting from deficiencies of lysosomal enzyme. Genotype-phenotype correlation is essential for timely and proper treatment allocation. Recently, by integrating prediction outcomes of 7 bioinformatics tools, we developed a SAAMP algorithm to predict the impact of individual amino acid substitution. To optimize this approach, we evaluated the performance of these bioinformatics tools in a broad array of genes. PolyPhen and PROVEAN had the best performances, while SNP&GOs, PANTHER and I-Mutant had the worst performances. Therefore, SAA...
Source: Clinical Genetics - February 2, 2018 Category: Genetics & Stem Cells Authors: Ou L, Przybilla MJ, Whitley CB Tags: Clin Genet Source Type: research

De novo variants in CDK13 associated with syndromic ID/DD; molecular and clinical delineation of 15 individuals and a further review.
, Stegmann APA, de Vries BBA, Schuurs-Hoeijmakers JHM Abstract De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of fifteen individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe two nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of two aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individu...
Source: Clinical Genetics - February 2, 2018 Category: Genetics & Stem Cells Authors: van den Akker WMR, Brummelman I, Martis LM, Timmermans RN, Pfundt R, Kleefstra T, Willemsen MH, Gerkes EH, Herkert JC, van Essen AJ, Rump P, Vansenne F, Terhal PA, van Haelst MM, Cristian I, Turner CE, Cho MT, Begtrup A, Willaert R, Fassi E, van Gassen KL Tags: Clin Genet Source Type: research

Lack of clear and univocal genotype-phenotype correlation in Familial Mediterranean Fever patients: A systematic review.
Abstract Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease. To date, following the isolation of more than 280 MEFV sequence variants, the genotype-phenotype correlation in FMF patients has been intensively investigated, however, an univocal and clear consensus has not been yet reached. Thus, the aim of this systematic review was to analyse the available literature findings in order to provide to scientific community an indirect estimation of the impact of genetic factors on the phenotypic variability of FMF. This systematic review has been conducted according to the...
Source: Clinical Genetics - February 2, 2018 Category: Genetics & Stem Cells Authors: Gangemi S, Manti S, Procopio V, Casciaro M, Di Salvo E, Cutrupi M, Ganci G, Salpietro C, Chimenz R, Cuppari C Tags: Clin Genet Source Type: research

Worldwide distribution of common IDUA pathogenic variants.
In conclusion, the most common pathogenic IDUA variant in MPS I patients are p.Trp402Ter, p.Gln70Ter and p.Pro533Arg. Knowledge about the genetic background of MPS I for each population is essential when developing new genotype-targeted therapies, as well as to enable faster genetic analysis and improve patient management. PMID: 29393969 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 2, 2018 Category: Genetics & Stem Cells Authors: Poletto E, Pasqualim G, Giugliani R, Matte U, Baldo G Tags: Clin Genet Source Type: research

Expanding the clinical and genetic spectra of NKX6-2-related disorder.
Abstract Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system, and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6-2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole exome or whole genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6-2 in three and two unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients shar...
Source: Clinical Genetics - February 1, 2018 Category: Genetics & Stem Cells Authors: Baldi C, Bertoli-Avella AM, Al-Sannaa N, Alfadhel M, Al-Thilhi K, Alameer S, Elmonairy AA, Al Shamsi AM, Abdelrahman HA, Al-Gazali L, Shawli A, Al Hakami F, Yavuz H, Kandaswamy KK, Rolfs A, Brandau O, Bauer P Tags: Clin Genet Source Type: research

Disclosure of Cardiac Variants of Uncertain Significance Results in an Exome Cohort.
This study examined the impact of disclosing sub-classifications of genetic variants of uncertain significance (VUS) on behavioral intentions. We studied return of VUS results to 79 individuals with a cardiomyopathy-associated VUS, sub-classified into VUS-high or VUS-low. Primary outcomes were perceived risk (absolute and comparative), perceived severity, perceived value of information, self-efficacy, decision regret, and behavioral intentions to share results and change behaviors. There was no significant difference between the two sub-classes in overall behavioral intentions (t=0.023, p=0.982) and each of the individual ...
Source: Clinical Genetics - January 31, 2018 Category: Genetics & Stem Cells Authors: Lawal TA, Lewis KL, Johnston JJ, Heidlebaugh AR, Ng D, Gaston-Johansson FG, Klein WMP, Biesecker BB, Biesecker LG Tags: Clin Genet Source Type: research

Three-dimensional genome architecture in health and disease.
Abstract More than a decade of massive DNA sequencing efforts has generated a large body of genomic, transcriptomic and epigenomic information that has provided a more and more detailed view of the functional elements and transactions within the human genome. Considerable efforts have also focused on linking these elements with one another by mapping their interactions and by establishing 3D genomic landscapes in various cell and tissue types. In parallel, multiple studies have associated genomic deletions, duplications and other rearrangements with human pathologies. In this review, we explore recent progresses t...
Source: Clinical Genetics - January 29, 2018 Category: Genetics & Stem Cells Authors: Ouimette JF, Rougeulle C, Veitia RA Tags: Clin Genet Source Type: research

Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants.
Abstract Identification of a novel compound heterozygous of GNB5 in a patient with intellectual developmental disorder with cardiac arrhytmia (IDDCA), from non-consaguineous family. Three-dimensional modelling and in silico predictions suggest that GNB5 variants are causative of the phenotype, extending the number of IDDCA patients so far identified. PMID: 29368331 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - January 25, 2018 Category: Genetics & Stem Cells Authors: Vernon H, Cohen J, De Nittis P, Fatemi A, McClellan R, Goldstein A, Malerba N, Guex N, Reymond A, Merla G Tags: Clin Genet Source Type: research

Are all Xq26.2 duplications overlapping GPC3 on array-CGH a cause of Simpson-Golabi-Behmel syndrome? When do we need transcript analysis?
PMID: 29372559 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - January 25, 2018 Category: Genetics & Stem Cells Authors: Vuillaume ML, Moizard MP, Hammouche E, Delrue MA, Perrin L, Maftei C, Dupont C, Drunat S, Cottereau E, Baumann C, Toutain A Tags: Clin Genet Source Type: research

Tylosis associated with squamous cell carcinoma of the oesophagus (TOC): Report of an African family with a novel RHBDF2 variant.
PMID: 29372562 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - January 25, 2018 Category: Genetics & Stem Cells Authors: Mokoena T, Smit JGM, Karusseit VO, Dorfling CM, van Rensburg EJ Tags: Clin Genet Source Type: research

Autosomal dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation.
This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations. PMID: 29364500 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - January 24, 2018 Category: Genetics & Stem Cells Authors: Napolitano F, Di Iorio V, Testa F, Tirozzi A, Reccia MG, Lombardi L, Farina O, Simonelli F, Gianfrancesco F, Di Iorio G, Melone MAB, Esposito T, Sampaolo S Tags: Clin Genet Source Type: research

WNT10B mutations associated with isolated dental anomalies.
Abstract Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In seven families afflicted with dental anomalies we detected four heterozygous missense variants in ...
Source: Clinical Genetics - January 24, 2018 Category: Genetics & Stem Cells Authors: Kantaputra PN, Hutsadaloi A, Kaewgahya M, Intachai W, German R, Koparal M, Leethanakul C, Tolun A, Ketudat Cairns JR Tags: Clin Genet Source Type: research

NDUFAF3 Variants that Disrupt Mitochondrial Complex I Assembly may associate with Cavitating Leukoencephalopathy.
We present a one-year-old girl with consciousness disturbance after a respiratory infection. Brain MRI revealed leukoencephalopathy with bilaterally symmetrical hyperintensity in the substantia nigra, medial thalamic nuclei, and basal nuclei, as well as cavities in the cerebral white matter and corpus callosum. Lactate levels in the spinal fluid were high, while magnetic resonance spectroscopy of the cerebral white matter and basal nuclei showed high peak lactate levels, suggesting mitochondrial dysfunction. The respiratory enzyme activity of complex I was reduced to 17-21% in skeletal muscle. Whole exome sequencing identi...
Source: Clinical Genetics - January 17, 2018 Category: Genetics & Stem Cells Authors: Ishiyama A, Muramatsu K, Uchino S, Sakai C, Matsushima Y, Makioka N, Ogata T, Suzuki E, Komaki H, Sasaki M, Mimaki M, Goto YI, Nishino I Tags: Clin Genet Source Type: research

Expanding the phenotype of SLC25A42-associated mitochondrial encephalomyopathy.
In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy. Our report confirms the link between SLC25A42 and mitochondrial disease in humans, and suggests that pathogenic variants in SLC25A42 should be interpreted with the understanding that the associated phenotype may be highly variable. PMID: 29327420 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - January 12, 2018 Category: Genetics & Stem Cells Authors: Almannai M, Alsamri A, Alqasmi A, Faqeih E, AlMutairi F, Alotaibi M, Samman MM, Eyaid W, Aljadhai YI, Shamseldin HE, Craigen W, Alkuraya FS Tags: Clin Genet Source Type: research

Genetics of patella hypoplasia/agenesis.
Abstract The patella is a sesamoid bone, crucial for knee stability. When absent or hypoplastic, recurrent knee subluxations, patello-femoral dysfunction and early gonarthrosis may occur. Patella hypoplasia/agenesis may be isolated or observed in syndromic conditions, either as the main clinical feature (Nail-Patella syndrome, Small Patella syndrome), as a clue feature which can help diagnosis assessment, or as a background feature that may be disregarded. Even in the latter, the identification of patella anomalies is important for an appropriate patient management. We review the clinical characteristics of these ...
Source: Clinical Genetics - January 11, 2018 Category: Genetics & Stem Cells Authors: Vanlerberghe C, Boutry N, Petit F Tags: Clin Genet Source Type: research

Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.
We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in two unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122 - 1/38) with an estimated newborn incidence of 1 in 18496 (95% CI; 1/59536 - 1/5776). Affected infa...
Source: Clinical Genetics - January 10, 2018 Category: Genetics & Stem Cells Authors: Meldau S, De Lacy R, Riordan G, Goddard E, Pillay K, Fieggen K, Marais D, Van der Watt G Tags: Clin Genet Source Type: research

UK Families with Children with Rare Chromosome Disorders: Changing Experiences of Diagnosis and Counseling (2003 to 2013).
We report the findings of two large-scale surveys, undertaken by the UK RCD Support Group Unique, of these families' experiences over a ten year period. Seven stages of the patient journey were examined. From pre-testing, through diagnosis, genetics consultation, clinical follow-up and peer support. Overall, 1,158 families replied; 36.4% response rate (2003) and 53.6% (2013). Analysis of responses identifies significant differences (p
Source: Clinical Genetics - January 10, 2018 Category: Genetics & Stem Cells Authors: Szczepura A, Wynn S, Searle B, Khan AJ, Palmer T, Biggerstaff D, Elliott J, Hultén MA Tags: Clin Genet Source Type: research

Patient actions and reactions after receiving negative results from expanded carrier screening.
Abstract With the expansion of carrier screening to general preconception and prenatal patient populations, most patients will receive negative results, which we define as indicating
Source: Clinical Genetics - January 2, 2018 Category: Genetics & Stem Cells Authors: Kraft SA, Schneider JL, Leo MC, Kauffman TL, Davis JV, Porter KM, McMullen CK, Wilfond BS, Goddard KAB Tags: Clin Genet Source Type: research

Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.
lin B PMID: 29286531 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - December 29, 2017 Category: Genetics & Stem Cells Authors: Tumienė B, Maver A, Writzl K, Hodzić A, Čuturilo G, Kuzmanić-Šamija R, Čulić V, Peterlin B Tags: Clin Genet Source Type: research

The Changing Landscape of Lynch Syndrome due to PMS2 Mutations.
Abstract DNA repair pathways are essential for cellular survival as our DNA is constantly under assault from both exogenous and endogenous DNA damaging agents. Five major mammalian DNA repair pathways exist within a cell to maintain genomic integrity. Of these, the DNA mismatch repair (MMR) pathway is highly conserved among species and is well documented in bacteria. In humans, the importance of MMR is underscored by the discovery that a single mutation in any one of four genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS). LS is an autosomal dominant condition that predisposes ...
Source: Clinical Genetics - December 29, 2017 Category: Genetics & Stem Cells Authors: Blount J, Prakash A Tags: Clin Genet Source Type: research

Homozygous TMEM127-mutations in two patients with bilateral pheochromocytomas.
Abstract Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL susceptibility genes with an autosomal dominant inheritance pattern. Here we report two patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year old mentally retarded patient the homozygous c.410-2A>G mutation was discovered during an update of DNA-analysis. A 26-year old mentally retarded patient was found to have a homozygous c.3G>A mutation. The parents of both patien...
Source: Clinical Genetics - December 28, 2017 Category: Genetics & Stem Cells Authors: Eijkelenkamp K, Olderode-Berends MJW, van der Luijt RB, Robledo M, van Dooren M, Feelders RA, de Vries J, Kerstens MN, Links TP, van der Horst-Schrivers ANA Tags: Clin Genet Source Type: research

Leucocytes Mutation load Declines with Age in Carriers of the m.3243A > G Mutation. A 10-year Prospective Cohort.
Leucocytes Mutation load Declines with Age in Carriers of the m.3243A>G Mutation. A 10-year Prospective Cohort. Clin Genet. 2017 Dec 20;: Authors: Langdahl JH, Larsen M, Frost M, Andersen PH, Yderstraede KB, Vissing J, Dunø M, Thomassen M, Frederiksen AL Abstract Carriers of the mitochondrial mutation m.3243A>G presents highly variable phenotypes including mitochondrial encephalomyopaty, lactoacidosis and stroke-like episodes (MELAS). We conducted a follow-up study to evaluate changes in leucocyte heteroplasmy and the clinical phenotypes in m.3243A>G carriers. Leucocyte heteroplasmy wa...
Source: Clinical Genetics - December 20, 2017 Category: Genetics & Stem Cells Authors: Langdahl JH, Larsen M, Frost M, Andersen PH, Yderstraede KB, Vissing J, Dunø M, Thomassen M, Frederiksen AL Tags: Clin Genet Source Type: research

Diagnostic exome sequencing in children: A survey of parental understanding, experience and psychological impact.
Abstract Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and psychological impact of CES by conducting a survey study of English-speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to hav...
Source: Clinical Genetics - December 20, 2017 Category: Genetics & Stem Cells Authors: Wynn J, Ottman R, Duong J, Wilson AL, Ahimaz P, Martinez J, Rabin R, Rosen E, Webster R, Au C, Cho MT, Egan C, Guzman E, Primiano M, Shaw JE, Sisson R, Klitzman RL, Appelbaum PS, Lichter-Konecki U, Anyane-Yeboa K, Iglesias A, Chung WK Tags: Clin Genet Source Type: research

Application of Next-Generation Sequencing (NGS) to improve cancer management: A review of the clinical effectiveness and cost-effectiveness.
We report the rate of successfully detecting mutations from the clinical studies. The Incremental Cost-Effectiveness Ratio and sensitivity analysis outcomes are reported for the cost-effectiveness articles. Fifty-six articles reported that sequencing patient samples using targeted gene panels, and 83% of the successfully sequenced patients harboured at least one mutation. Only six studies reported on the cost-effectiveness of the application of NGS in cancer care. NGS is an effective tool for identifying mutation in cancer patients. However, more rigorous cost-effectiveness studies of NGS applied to cancer management are n...
Source: Clinical Genetics - December 19, 2017 Category: Genetics & Stem Cells Authors: Tan O, Shrestha R, Cunich M, Schofield DJ Tags: Clin Genet Source Type: research

The alternatively spliced exon of COL5A1 is mutated in autosomal recessive classical Ehlers-Danlos syndrome.
PMID: 29250776 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - December 18, 2017 Category: Genetics & Stem Cells Authors: Alzahrani F, Alkeraye S, Alkuraya FS Tags: Clin Genet Source Type: research

De Novo Variants in KLF7 are a Potential Novel Cause of Developmental Delay/Intellectual Disability, Neuromuscular and Psychiatric Symptoms.
Abstract Due to small numbers of reported patients with pathogenic variants in single genes, the phenotypic spectrum associated with genes causing neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder is expanding. Among these genes is KLF7 (Krüppel-like factor 7), which is located at 2q33.3 and has been implicated in several developmental processes. KLF7 has been proposed to be a candidate gene for the phenotype of autism features seen in patients with a 2q33.3q34deletion. Herein, we report four unrelated individuals with de novo KLF7 missense variants who share simil...
Source: Clinical Genetics - December 18, 2017 Category: Genetics & Stem Cells Authors: Powis Z, Petrik I, Cohen JS, Escolar D, Burton J, van Ravenswaaij-Arts CMA, Sival DA, Stegmann APA, Kleefstra T, Pfundt R, Chikarmane R, Begtrup A, Huether R, Tang S, Shinde DN Tags: Clin Genet Source Type: research

How practical experiences, educational routes and multidisciplinary teams influence genetic counsellors' clinical practice in Europe.
tad C Abstract The main objective of our study was to explore whether, and to what extent, genetic counsellors' characteristics impact on their tasks in practice. Specifically, we explored the complementariness between genetic counsellors and medical geneticists and therefore looked at the most relevant tasks of genetic counsellors, according to genetic counsellors themselves and according to the medical geneticists they work with. 104 genetic counsellors and 29 medical geneticists from 15 countries completed a purposefully designed questionnaire. Results showed that most genetic counsellors in Europe perform simi...
Source: Clinical Genetics - December 18, 2017 Category: Genetics & Stem Cells Authors: Pestoff R, Moldovan R, Cordier C, Serra-Juhé C, Paneque M, Ingvoldstad C Tags: Clin Genet Source Type: research

Two patients with PNKP mutations presenting with microcephaly, seizure, and oculomotor apraxia.
PMID: 29243230 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - December 15, 2017 Category: Genetics & Stem Cells Authors: Taniguchi-Ikeda M, Morisada N, Inagaki H, Ouchi Y, Takami Y, Tachikawa M, Satake W, Kobayashi K, Tsuneishi S, Takada S, Yamaguchi H, Nagase H, Nozu K, Okamoto N, Nishio H, Toda T, Morioka I, Wada H, Kurahashi H, Iijima K Tags: Clin Genet Source Type: research

A de novo loss-of-function DYNC1H1 mutation in a patient with parkinsonian features and a favourable response to levodopa.
Abstract Graphical summary of 'A de novo loss-of-function DYNC1H1 mutation in a patient with parkinsonian features and a favourable response to levodopa' by Szczałuba et al.. PMID: 29243232 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - December 15, 2017 Category: Genetics & Stem Cells Authors: Szczałuba K, Szymańska K, Rydzanicz M, Ciara E, Walczak A, Piekutowska-Abramczuk D, Kosińska J, Jacoszek A, Czerska K, Biernacka A, Laure-Kamionowska M, Gasperowicz P, Pronicka E, Płoski R Tags: Clin Genet Source Type: research

Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion.
We present eight unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with six previously reported cases, we present a case series of seven female and seven male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunol...
Source: Clinical Genetics - December 14, 2017 Category: Genetics & Stem Cells Authors: Chiu ATG, Pei SLC, Mak CCY, Leung GKC, Yu MHC, Lee SL, Vreeburg M, Pfundt R, van der Burgt I, Kleefstra T, Frederic TM, Nambot S, Faivre L, Bruel AL, Rossi M, Isidor B, Küry S, Cogne B, Besnard T, Willems M, Reijnders MRF, Chung BHY Tags: Clin Genet Source Type: research

Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA Related Overgrowth Spectrum (PROS).
Abstract Congenital Lipomatous Overgrowth with Vascular, Epidermal, and Skeletal anomalies (CLOVES) and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of-function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3-kinase. Affected tissue is needed to find mutations, since mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet di...
Source: Clinical Genetics - December 12, 2017 Category: Genetics & Stem Cells Authors: Michel ME, Konczyk DJ, Yeung KS, Murillo R, Vivero MP, Hall AM, Zurakowski D, Adams D, Gupta A, Huang AY, Chung BHY, Warman ML Tags: Clin Genet Source Type: research

Phenotype expansion and development in Kosaki Overgrowth Syndrome.
sek M Abstract We expand the KOGS phenotype by over 70% to include 24 unreported KOGS symptoms, in a first male patient, the third overall associated with the PDGFRB c.1751C>G, p.(Pro584Arg) mutation. 18 of these symptoms are unique to our patient, the remaining 6 are shared with other patients. Of the 24 unreported features overall, 6 show marked phenotype evolution and varying time of onset. The triangular face detected at 14 months and long palpebral fissures with lateral ectropion at 4 years are present in other members of the cohort. The remaining 4 are unique to Patient 5: pronounced macrocephaly from bir...
Source: Clinical Genetics - December 11, 2017 Category: Genetics & Stem Cells Authors: Gawliński P, Pelc M, Ciara E, Jhangiani S, Jurkiewicz E, Gambin T, Różdżyńska-Świątkowska A, Dawidziuk M, Akdemir ZHC, Guilbride DL, Muzny D, Lupski JR, Krajewska-Walasek M Tags: Clin Genet Source Type: research

Collective effects of common SNPs and genetic risk prediction in type 1 diabetes.
Abstract Type 1 diabetes (T1D) is a common autoimmune disease and may be related to multiple genetic and environmental risk factors. Previous genetic studies have focused on looking for individual polymorphic risk variants. Here we studied the overall levels of genetic diversity in T1D patients by making use of a previously published study including 1,865 cases and 2,828 reference samples with genotyping data for 500K common single nucleotide polymorphisms (SNPs). We determined the minor allele status of each SNP in the reference samples and calculated the total number of minor alleles or minor allele contents (MA...
Source: Clinical Genetics - December 8, 2017 Category: Genetics & Stem Cells Authors: Gui Y, Lei X, Huang S Tags: Clin Genet Source Type: research

Clinical sequencing: from raw data to diagnosis with lifetime value.
Abstract High-throughput sequencing (HTS) has revolutionized genetics by enabling the detection of sequence variants at hitherto unprecedented large scale. Despite these advances, however, there are still remaining challenges in the complete coverage of targeted regions (genes, exome or genome) as well as in HTS data analysis and interpretation. Moreover, it is easy to get overwhelmed by the plethora of available methods and tools for HTS. Here, we review the step-by-step process from the generation of sequence data to molecular diagnosis of Mendelian diseases. Highlighting advantages and limitations, this review ...
Source: Clinical Genetics - December 5, 2017 Category: Genetics & Stem Cells Authors: Caspar SM, Dubacher N, Kopps AM, Meienberg J, Henggeler C, Matyas G Tags: Clin Genet Source Type: research

A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly.
This study focuses on anencephaly, which despite having a similar frequency to spina bifida and being the most common type of NTD observed in mouse models, has had more limited inclusion in genetic studies. A genetic influence is strongly implicated in determining risk of NTDs and a molecular diagnosis is of fundamental importance to families both in terms of understanding the origin of the condition and for managing future pregnancies. Here we used a custom panel of 191 NTD candidate genes to screen 90 patients with cranial NTDs (n=85 anencephaly and n=5 craniorachischisis) with a targeted exome sequencing platform. After...
Source: Clinical Genetics - December 4, 2017 Category: Genetics & Stem Cells Authors: Ishida M, Cullup T, Boustred C, James C, Docker J, English C, GOSgene, Lench N, Copp AJ, Moore GE, Greene NDE, Stanier P Tags: Clin Genet Source Type: research

Genetic association of molecular traits: a help to identify causative variants in complex diseases.
Abstract In the past 15 years, major progresses have been made in the understanding of the genetic basis of regulation of gene expression. These new insights have revolutionized our approach to resolve the genetic variation underlying complex diseases. Gene transcript levels were the first expression phenotypes that were studied. They are heritable and therefore amenable to genome-wide association studies (GWAS). The genetic variants that modulate them are called expression quantitative trait loci (eQTL). Their study has been extended to other molecular quantitative trait loci (molQTL) that regulate gene expressio...
Source: Clinical Genetics - December 1, 2017 Category: Genetics & Stem Cells Authors: Vandiedonck C Tags: Clin Genet Source Type: research

Osteopathia striata with cranial sclerosis and Wilms tumor: Coincidence or consequence?
PMID: 29120061 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - November 11, 2017 Category: Genetics & Stem Cells Authors: Sperotto F, Bisogno G, Opocher E, Rossi S, Rigon C, Trevisson E, Mercolini F Tags: Clin Genet Source Type: research

Small patella syndrome: New clinical and molecular insights into a consistent phenotype.
PMID: 29120062 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - November 11, 2017 Category: Genetics & Stem Cells Authors: Vanlerberghe C, Jourdain AS, Dieux A, Toutain A, Callewaert B, Dupuis-Girod S, Unger S, Wright M, Isidor B, Ghoumid J, Petit F, Boutry N, Escande F, Manouvrier-Hanu S Tags: Clin Genet Source Type: research

A novel germline mutation in CDK4 codon 24 associated to familial melanoma.
PMID: 29124743 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - November 10, 2017 Category: Genetics & Stem Cells Authors: Bottillo I, La Starza R, Radio FC, Molica C, Pedace L, Pierini T, De Bernardo C, Stingeni L, Bargiacchi S, Paiardini A, Janson G, Mecucci C, Grammatico P Tags: Clin Genet Source Type: research