Novel mutation of FKBP10 in a pediatric patient with osteogenesis imperfecta type XI identified by clinical exome sequencing.

Appl Clin Genet. 2017;10:75-83

Authors: Velasco HM, Morales JL

Abstract
Osteogenesis imperfecta (OI) is a hereditary disease characterized by bone fragility caused by mutations in the proteins that support the formation of the extracellular matrix in the bone. The diagnosis of OI begins with clinical suspicion, from phenotypic findings at birth, low-impact fractures during childhood or family history that may lead to it. However, the variability in the semiology of the disease does not allow establishing an early diagnosis in all cases, and unfortunately, specific clinical data provided by the literature only report 28 patients with OI type XI. This information is limited and heterogeneous, and therefore, detailed information on the natural history of this disease is not yet available. This paper reports the case of a male patient who, despite undergoing multidisciplinary management, did not have a diagnosis for a long period of time, and could only be given one with the use of whole-exome sequencing. The use of the next-generation sequencing in patients with ultrarare genetic diseases, including skeletal dysplasias, should be justified when clear clinical criteria and an improvement in the quality of life of the patients and their families are intended while reducing economic and time costs. Thus, this case report corresponds to the 29th patient affected with OI type XI, and the 18th mutation in FKBP10, causative of this pathology.

PMID: 29158687 [PubMed]

Exome Pool-Seq in neurodevelopmental disorders.

Eur J Hum Genet. 2017 Nov 20;:

Authors: Popp B, Ekici AB, Thiel CT, Hoyer J, Wiesener A, Kraus C, Reis A, Zweier C

Abstract
High throughput sequencing has greatly advanced disease gene identification, especially in heterogeneous entities. Despite falling costs this is still an expensive and laborious technique, particularly when studying large cohorts. To address this problem we applied Exome Pool-Seq as an economic and fast screening technology in neurodevelopmental disorders (NDDs). Sequencing of 96 individuals can be performed in eight pools of 12 samples on less than one Illumina sequencer lane. In a pilot study with 96 cases we identified 27 variants, likely or possibly affecting function. Twenty five of these were identified in 923 established NDD genes (based on SysID database, status November 2016) (ACTB, AHDC1, ANKRD11, ATP6V1B2, ATRX, CASK, CHD8, GNAS, IFIH1, KCNQ2, KMT2A, KRAS, MAOA, MED12, MED13L, RIT1, SETD5, SIN3A, TCF4, TRAPPC11, TUBA1A, WAC, ZBTB18, ZMYND11), two in 543 (SysID) candidate genes (ZNF292, BPTF), and additionally a de novo loss-of-function variant in LRRC7, not previously implicated in NDDs. Most of them were confirmed to be de novo, but we also identified X-linked or autosomal-dominantly or autosomal-recessively inherited variants. With a detection rate of 28%, Exome Pool-Seq achieves comparable results to individual exome analyses but reduces costs by >85%. Compared with other large scale approaches using Molecular Inversion Probes (MIP) or gene panels, it allows flexible re-analysis of data. Exome Pool-Seq is thus well suited for large-scale, cost-efficient and flexible screening in characterized but heterogeneous entities like NDDs.

PMID: 29158550 [PubMed - as supplied by publisher]

FBN3 gene involved in pathogenesis of a Chinese family with Bardet-Biedl syndrome.

Oncotarget. 2017 Oct 17;8(49):86718-86725

Authors: Wang Y, Garraoui A, Zeng L, Lai M, He F, Wang H, Jiang C, Chen Y, Dai L, Fan N, Yang H, Zhang J, Liu X

Abstract
Purpose: This study was designed to evaluate the molecular genetics of a Chinese family with Bardet-Biedl syndrome (BBS).
Methods: All the family members underwent medical history evaluation, ophthalmologic and physical examinations. Whole exome sequencing was performed on two affected individuals and their parents. All variants were verified in all family members by PCR amplification and Sanger sequencing.
Results: Patients in this family were diagnosed as Bardet-Biedl syndrome, with an inheritance pattern of autosomal recessive. Compound heterozygous mutations of the FBN3 gene (c.3616G>A and c.6037C>T) were identified by whole exome sequencing. Results from Sanger sequencing showed co-segregation of these compound heterozygous mutations in the FBN3 gene with BBS disease in the family.
Conclusion: Novel compound heterozygous mutations c.3616G>A and c.6037C>T of FBN3 were identified in all affected individuals but not in the unaffected family members. This is the first time to the best of our knowledge, that the FBN3 gene is involved in the pathogenesis of BBS. This study will expand our understanding about the gene spectrum related to this genetically heterogeneous disorder.

PMID: 29156830 [PubMed]

Analysis of an ADTKD family with a novel frameshift mutation in MUC1 reveals characteristic features of mutant MUC1 protein.

Nephrol Dial Transplant. 2017 Jun 01;:

Authors: Yamamoto S, Kaimori JY, Yoshimura T, Namba T, Imai A, Kobayashi K, Imamura R, Ichimaru N, Kato K, Nakaya A, Takahara S, Isaka Y

Abstract
Background: Medullary cystic kidney disease Type 1 is an autosomal dominant tubulointerstitial kidney disease (ADTKD). Recently, mucin 1 ( MUC1 ) was identified as a causal gene of medullary cystic kidney disease (ADTKD-MUC1). However, the MUC1 mutation was found to be a single cytosine insertion in a single copy of the GC-rich variable number of tandem repeats (VNTRs), which are very difficult to analyze by next-generation sequencing. To date, other mutations have not been detected in ADTKD-MUC1, and the mutant MUC1 protein has not been analyzed because of the difficulty of genetically modifying the VNTR sequence.
Methods: We conducted whole-exome analyses of an ADTKD family by next-generation sequencing. We also performed histopathological analyses of a renal biopsy from a pedigree family member. We constructed a mutant protein expression vector based on the patient genome sequence and characterized the nature of the mutant protein.
Results: We found a novel frameshift mutation before the VNTR in the MUC1 gene. The resulting mutant MUC1 protein had a very similar amino acid sequence and predicted 3D structure to the previously reported mutant protein. Notably, the recombinant mutant MUC1 protein was trapped in the cytoplasm and appeared to self-aggregate. The patient native mutant protein was also found in urine exosomes.
Conclusions: This novel frameshift mutation in the MUC1 gene and consequent mutant protein may contribute to the future discovery of the pathophysiology of ADTKD-MUC1. The mutant MUC1 protein in urine exosomes may be used for non-DNA-related diagnosis.

PMID: 29156055 [PubMed - as supplied by publisher]

RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Mao H, Yang W, Latour S, Yang J, Winter S, Zheng J, Ni K, Lv M, Liu C, Huang H, Chan KW, Pui-Wah Lee P, Tu W, Fischer A, Lau YL

Abstract
BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired apoptosis. It was initially regarded as a very rare disease, but recent studies show it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of ALPS patients, but around one third of such patients remain undefined genetically.
OBJECTIVE: We described two siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype.
METHODS: Whole exome sequencing, molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported.
RESULTS: The two patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, presence of ANA and other autoantibodies, but normal double negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the two siblings. The mutations impaired TCR signaling, leading to defective T cell activation and proliferation, as well as impaired activation-induced cell death of T cells.
CONCLUSION: This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the TCR signaling pathway in similar patients but with unknown genetic cause.

PMID: 29155103 [PubMed - as supplied by publisher]

Novel mosaic variants in two patients with Cornelia de Lange syndrome.

Eur J Med Genet. 2017 Nov 15;:

Authors: Pozojevic J, Parenti I, Graul-Neumann L, Ruiz Gil S, Watrin E, Wendt KS, Werner R, Strom TM, Gillessen-Kaesbach G, Kaiser FJ

Abstract
Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder caused by mutations in genes that encode for either structural (SMC1A, SMC3, RAD21) or regulatory (NIPBL, HDAC8) subunits of the cohesin complex. NIPBL represents the major gene of the syndrome and heterozygous mutations can be identified in more than 65% of patients. Interestingly, large portions of these variants were described as somatic mosaicism and often escape standard molecular diagnostics using lymphocyte DNA. Here we discuss the role of somatic mosaicism in CdLS and describe two additional patients with NIPBL mosaicism detected by targeted gene panel or exome sequencing. In order to verify the next generation sequencing data, Sanger sequencing or pyrosequencing on DNA extracted from different tissues were applied. None of the pathogenic variants was originally detected by Sanger sequencing on blood DNA. Patient 1 displays an unusual combination of clinical features: he is cognitively only mildly affected, but shows severe limb reduction defects. The second patient presents with a moderate phenotype. Interestingly, Sanger sequencing analysis on fibroblast DNA did not detect the disease-causing variant previously observed on the same DNA sample by exome sequencing. Subsequent analyses could confirm the variants by Sanger sequencing on buccal mucosa DNA. Notably, this is the first report of a higher mutational load in buccal mucosa than in fibroblast cells of a CdLS patient. Detection of low-level mosaicism is of utmost importance for an accurate molecular diagnosis and a proper genetic counseling of patients with a clinical diagnosis of CdLS. Next-generation sequencing technologies greatly facilitate the detection of low-level mosaicism, which might otherwise remain undetected by conventional sequencing approaches.

PMID: 29155047 [PubMed - as supplied by publisher]

Identification of de novo germline mutations and causal genes for sporadic diseases using trio-based whole-exome/genome sequencing.

Biol Rev Camb Philos Soc. 2017 Nov 20;:

Authors: Jin ZB, Li Z, Liu Z, Jiang Y, Cai XB, Wu J

Abstract
Whole-genome or whole-exome sequencing (WGS/WES) of the affected proband together with normal parents (trio) is commonly adopted to identify de novo germline mutations (DNMs) underlying sporadic cases of various genetic disorders. However, our current knowledge of the occurrence and functional effects of DNMs remains limited and accurately identifying the disease-causing DNM from a group of irrelevant DNMs is complicated. Herein, we provide a general-purpose discussion of important issues related to pathogenic gene identification based on trio-based WGS/WES data. Specifically, the relevance of DNMs to human sporadic diseases, current knowledge of DNM biogenesis mechanisms, and common strategies or software tools used for DNM detection are reviewed, followed by a discussion of pathogenic gene prioritization. In addition, several key factors that may affect DNM identification accuracy and causal gene prioritization are reviewed. Based on recent major advances, this review both sheds light on how trio-based WGS/WES technologies can play a significant role in the identification of DNMs and causal genes for sporadic diseases, and also discusses existing challenges.

PMID: 29154454 [PubMed - as supplied by publisher]

Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.

Lancet Neurol. 2017 Nov 16;:

Authors: Chia R, Chiò A, Traynor BJ

Abstract
BACKGROUND: The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS.
RECENT DEVELOPMENTS: Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. WHERE NEXT?: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management.

PMID: 29154141 [PubMed - as supplied by publisher]

Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases.

NPJ Genom Med. 2017;2:

Authors: Schofield D, Alam K, Douglas L, Shrestha R, MacArthur DG, Davis M, Laing NG, Clarke NF, Burns J, Cooper ST, North KN, Sandaradura SA, O'Grady GL

Abstract
Childhood-onset muscle disorders are genetically heterogeneous. Diagnostic workup has traditionally included muscle biopsy, protein-based studies of muscle specimens, and candidate gene sequencing. High throughput or massively parallel sequencing is transforming the approach to diagnosis of rare diseases; however, evidence for cost-effectiveness is lacking. Patients presenting with suspected congenital muscular dystrophy or nemaline myopathy were ascertained over a 15-year period. Patients were investigated using traditional diagnostic approaches. Undiagnosed patients were investigated using either massively parallel sequencing of a panel of neuromuscular disease genes panel, or whole exome sequencing. Cost data were collected for all diagnostic investigations. The diagnostic yield and cost effectiveness of a molecular approach to diagnosis, prior to muscle biopsy, were compared with the traditional approach. Fifty-six patients were analysed. Compared with the traditional invasive muscle biopsy approach, both the neuromuscular disease panel and whole exome sequencing had significantly increased diagnostic yields (from 46 to 75% for the neuromuscular disease panel, and 79% for whole exome sequencing), and reduced the cost per diagnosis from USD$16,495 (95% CI: $12,413-$22,994) to USD$3706 (95% CI: $3086-$4453) for the neuromuscular disease panel and USD $5646 (95% CI: $4501-$7078) for whole exome sequencing. The neuromuscular disease panel was the most cost-effective, saving USD$17,075 (95% CI: $10,654-$30,064) per additional diagnosis, over the traditional diagnostic pathway. Whole exome sequencing saved USD$10,024 (95% CI: $5795-$17,135) per additional diagnosis. This study demonstrates the cost-effectiveness of investigation using massively parallel sequencing technologies in paediatric muscle disease. The findings emphasise the value of implementing these technologies in clinical practice, with particular application for diagnosis of Mendelian diseases, and provide evidence crucial for government subsidy and equitable access.

PMID: 29152331 [PubMed]

Recent therapeutic advances in chronic lymphocytic leukemia.

F1000Res. 2017;6:1924

Authors: Bose P, Gandhi V

Abstract
The last several years have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL). The course of this very heterogeneous disease, traditionally treated with chemotherapeutic agents usually in combination with rituximab, typically has been characterized by remissions and relapses, and survival times vary greatly, depending on intrinsic biological attributes of the leukemia. The developments of the last few years have been transformative, ushering in an era of novel, molecularly targeted therapies, made possible by extensive efforts to elucidate the biology of the disease that predated the new targeted drugs. Thus, successful therapeutic targeting of the B-cell receptor signaling pathway and of the Bcl-2 anti-apoptotic protein with small molecules has now made chemotherapy-free approaches possible, hopefully mitigating the risk of development of therapy-related myeloid neoplasms and making eventual cure of CLL with the use of optimal drug combinations a realistic goal. Most importantly, these therapies have demonstrated unprecedented efficacy in patients with deletion 17p/TP53 mutation, a subset that historically has been very difficult to treat. However, as we gain more experience with the newer agents, unique safety concerns and resistance mechanisms have emerged, as has the issue of cost, as these expensive drugs are currently administered indefinitely. Accordingly, novel laboratory-based strategies and clinical trial designs are being explored to address these issues. The availability of whole exome/genome sequencing has given us profound insights into the mutational landscape of CLL. In this article, we highlight some of the most impactful advances since this topic was last reviewed in this journal.

PMID: 29152232 [PubMed]

Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese.

Genome Med. 2017 Nov 17;9(1):97

Authors: Gratten J, Zhao Q, Benyamin B, Garton F, He J, Leo PJ, Mangelsdorf M, Anderson L, Zhang ZH, Chen L, Chen XD, Cremin K, Deng HW, Edson J, Han YY, Harris J, Henders AK, Jin ZB, Li Z, Lin Y, Liu X, Marshall M, Mowry BJ, Ran S, Reutens DC, Song S, Tan LJ, Tang L, Wallace RH, Wheeler L, Wu J, Yang J, Xu H, Visscher PM, Bartlett PF, Brown MA, Wray NR, Fan D

Abstract
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals.
METHODS: WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10(-5) in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls.
RESULTS: No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10(-12)), SOD1 (p = 8.9 × 10(-9)) and NEK1 (p = 1.1 × 10(-9)). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10(-3), respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14).
CONCLUSIONS: While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.

PMID: 29149916 [PubMed - in process]

Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness.

Orphanet J Rare Dis. 2017 Nov 17;12(1):173

Authors: Johnson K, Töpf A, Bertoli M, Phillips L, Claeys KG, Stojanovic VR, Perić S, Hahn A, Maddison P, Akay E, Bastian AE, Łusakowska A, Kostera-Pruszczyk A, Lek M, Xu L, MacArthur DG, Straub V

Abstract
BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants.
RESULTS: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13 T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease.
CONCLUSIONS: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders.

PMID: 29149851 [PubMed - in process]

Other autoinflammatory disease genes in an FMF-prevalent population: a homozygous MVK mutation and a novel heterozygous TNFRSF1A mutation in two different Turkish families with clinical FMF.

Clin Exp Rheumatol. 2017 Oct 27;

Authors: Karacan İ, Uğurlu S, Tolun A, Tahir Turanlı E, Özdoğan H

Abstract
OBJECTIVES: No MEFV mutations are detected in approximately 10% of the patients with clinical FMF in populations where the disease is highly prevalent. Causative mutations were searched in other genes in two such families with "MEFV negative clinical FMF".
METHODS: Father and daughter of family A had attacks of fever, abdominal pain and AA amyloidosis. The two sibs of family B complained of febrile episodes with abdominal pain and arthritis. The patients were clinically investigated. Exome analysis in the daughter in family A and linkage analysis and candidate gene sequencing for the members of family B were performed. All patients were re-evaluated in the light of the genetic findings.
RESULTS: In the daughter in family A, filtering of the exome file for variants in 25 autoimmune/inflammatory disease-related genes revealed two heterozygous missense variants in TNFRSF1A, novel p.Cys72Phe and frequent p.Arg121Gln. In family B, novel, homozygous missense p.Cys161Arg in MVK was identified. A clinical re-evaluation of the patients revealed a phenotype consistent with FMF rather than TRAPS in family A and an overlap of FMF with HIDS in family B.
CONCLUSIONS: In high risk populations of FMF a proportion of patients without MEFV mutations may carry causative mutations in other genes, and the clinical findings may not be fully consistent with the phenotype expected of the mutation identified but rather resemble FMF or an overlap syndrome.

PMID: 29148404 [PubMed - as supplied by publisher]

The Actionability of Exome sequencing testing results.

Sociol Health Illn. 2017 Nov;39(8):1542-1556

Authors: Stivers T, Timmermans S

Abstract
Genomic tests such as exome sequencing have recently become an option for diagnosing patients. The tests allow clinical geneticists to sequence the majority of patients' disease causing genetic variants. As a new technology, exome sequencing confronts the question of what the benefit is of this increased genetic information. Against a narrow perspective of clinical utility that emphasises tangible improvements in a patient's disease management, professional organisations have argued that genomic sequencing should be considered beneficial if it helps families and society. Based on video-recorded observations of the return of exome sequencing results to parents of a child with disabilities in the clinic and in-depth interviews with these parents, we examine how genomic test results become actionable in the clinical encounter. We find that parents and clinicians marshal exome results beyond biomedical diagnostic and management goals to address questions about guilt for causing the disabilities and to secure access to disability-related services. We argue that genomic actionability rests on the interaction between the biological characteristics of genetic results and the predicaments facing parents of children with disabilities.

PMID: 29148115 [PubMed - in process]

c.207C>G mutation in sepiapterin reductase causes autosomal dominant dopa-responsive dystonia.

Neurol Genet. 2017 Dec;3(6):e197

Authors: Shalash AS, Rösler TW, Müller SH, Salama M, Deuschl G, Müller U, Opladen T, Petersen BS, Franke A, Hopfner F, Kuhlenbäumer G, Höglinger GU

Abstract
Objective: To elucidate the genetic cause of an Egyptian family with dopa-responsive dystonia (DRD), a childhood-onset dystonia, responding therapeutically to levodopa, which is caused by mutations in various genes.
Methods: Rare variants in all coding exons of GCH1 were excluded by Sanger sequencing. Exome sequencing was applied for 1 unaffected and 2 affected family members. To investigate the functional consequences of detected genetic variants, urinary sepiapterin concentrations were determined by high-performance liquid chromatography.
Results: A heterozygous rare nonsynonymous variant in exon 1 of sepiapterin reductase (SPR, c.207C>G, p.Asp69Glu) was found in all affected family members. Urinary concentrations of sepiapterin were above the standard of normal controls in most SPR mutation carriers, suggesting functional biochemical consequences of the mutation. Variant filtering of all genes involved in the tetrahydrobiopterin pathway, required for levodopa synthesis, revealed an additional common variant in dihydrofolate reductase (DHFR, rs70991108). The presence of both variants was significantly stronger associated with the biochemical abnormality and the clinical disease state as opposed to 1 variant only.
Conclusions: The rare SPR mutation can cause autosomal dominant DRD with incomplete penetrance. The common DHFR variant might have synergistic effects on production of tetrahydrobiopterin and levodopa, thereby increasing penetrance.

PMID: 29147684 [PubMed]

A landscape of germline mutations in a cohort of inherited bone marrow failure patients.

Blood. 2017 Nov 16;:

Authors: Bluteau O, Sebert M, Leblanc T, Peffault de Latour R, Quentin S, Lainey E, Hernandez L, Dalle JH, Sicre de Fontbrune F, Lengline E, Itzykson R, Clappier E, Boissel N, Vasquez N, Da Costa M, Masliah-Planchon J, Cuccuini W, Raimbault A, De Jaegere L, Adès L, Fenaux P, Maury S, Schmitt C, Muller M, Domenech C, Blin N, Bruno B, Pellier I, Hunault M, Blanche S, Petit A, Leverger G, Michel G, Bertrand Y, Baruchel A, Socié G, Soulier J

Abstract
Bone marrow failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% bone marrow blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germline mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4) Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in IBMF, such as SAMD9 and SAMD9L (N=16 of the 86 patients; 18.6%), MECOM/EVI1 (N=6, 7.0%), and ERCC6L2 (N=7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, while MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly-recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

PMID: 29146883 [PubMed - as supplied by publisher]

Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants.

Genet Med. 2017 Nov 16;:

Authors: Xu C, Cassatella D, van der Sloot AM, Quinton R, Hauschild M, De Geyter C, Flück C, Feller K, Bartholdi D, Nemeth A, Halperin I, Pekic Djurdjevic S, Maeder P, Papadakis G, Dwyer AA, Marino L, Favre L, Pignatelli D, Niederländer NJ, Acierno J, Pitteloud N

Abstract
PurposeCongenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined.MethodsRare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype-phenotype correlations were evaluated.ResultsOf the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01).ConclusionPathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.Genetics in Medicine advance online publication, 16 November 2017; doi:10.1038/gim.2017.197.

PMID: 29144511 [PubMed - as supplied by publisher]

Polyglucosan myopathy and functional characterization of a novel GYG1 mutation.

Acta Neurol Scand. 2017 Nov 15;:

Authors: Hedberg-Oldfors C, Mensch A, Visuttijai K, Stoltenburg G, Stoevesandt D, Kraya T, Oldfors A, Zierz S

Abstract
OBJECTIVES: Disorders of glycogen metabolism include rare hereditary muscle glycogen storage diseases with polyglucosan, which are characterized by storage of abnormally structured glycogen in muscle in addition to exercise intolerance or muscle weakness. In this study, we investigated the etiology and pathogenesis of a late-onset myopathy associated with glycogenin-1 deficiency.
MATERIALS AND METHODS: A family with two affected siblings, 64- and 66-year-olds, was studied. Clinical examination and whole-body MRI revealed weakness and wasting in the hip girdle and proximal leg muscles affecting ambulation in the brother. The sister had weakness and atrophy of hands and slight foot dorsiflexion difficulties. Muscle biopsy and whole-exome sequencing were performed in both cases to identify and characterize the pathogenesis including the functional effects of identified mutations.
RESULTS: Both siblings demonstrated storage of glycogen that was partly resistant to alpha-amylase digestion. Both were heterozygous for two mutations in GYG1, one truncating 1-base deletion (c.484delG; p.Asp163Thrfs*5) and one novel missense mutation (c.403G>A; p.Gly135Arg). The mutations caused reduced expression of glycogenin-1 protein, and the missense mutation abolished the enzymatic function as analyzed by an in vitro autoglucosylation assay.
CONCLUSION: We present functional evidence for the pathogenicity of a novel GYG1 missense mutation located in the substrate binding domain. Our results also demonstrate that glycogenin-1 deficiency may present with highly variable distribution of weakness and wasting also in the same family.

PMID: 29143313 [PubMed - as supplied by publisher]

[Analysis of gene mutation of early onset epileptic spasm with unknown reason].

Zhonghua Er Ke Za Zhi. 2017 Nov 02;55(11):813-817

Authors: Yang X, Pan G, Li WH, Zhang LM, Wu BB, Wang HJ, Zhang P, Zhou SZ

Abstract
Objective: To summarize the gene mutation of early onset epileptic spasm with unknown reason. Method: In this prospective study, data of patients with early onset epileptic spasm with unknown reason were collected from neurological department of Children's Hospital of Fudan University between March 2016 and December 2016. Patients with known disorders such as infection, metabolic, structural, immunological problems and known genetic mutations were excluded. Patients with genetic disease that can be diagnosed by clinical manifestations and phenotypic characteristics were also excluded. Genetic research methods included nervous system panel containing 1 427 epilepsy genes, whole exome sequencing (WES), analysis of copy number variation (CNV) and karyotype analysis of chromosome. The basic information, phenotypes, genetic results and the antiepileptic treatment of patients were analyzed. Result: Nine of the 17 cases with early onset epileptic spasm were boys and eight were girls. Patients' age at first seizure onset ranged from 1 day after birth to 8 months (median age of 3 months). The first hospital visit age ranged from 1 month to 2 years (median age of 4.5 months). The time of following-up ranged from 8 months to 3 years and 10 months. All the 17 patients had early onset epileptic spasm. Video electroencephalogram was used to monitor the spasm seizure. Five patients had Ohtahara syndrome, 10 had West syndrome, two had unclear classification. In 17 cases, 10 of them had detected pathogenic genes. Nine cases had point mutations, involving SCN2A, ARX, UNC80, KCNQ2, and GABRB3. Except one case of mutations in GABRB3 gene have been reported, all the other cases had new mutations. One patient had deletion mutation in CDKL5 gene. One CNV case had 6q 22.31 5.5MB repeats. Ten cases out of 17 were using 2-3 antiepileptic drugs (AEDs) and the drugs had no effect. Seven cases used adrenocorticotropic hormone (ACTH) and prednisone besides AEDs (a total course for 8 weeks). Among them, five cases had no effect and two cases were seizure free recently. A case with GABRB3 (C.905A>G) had seizure controlled for 3 mouths. A case with ARX (C.700G>A) had seizure controlled for 6 mouths. Conclusion: The early onset epileptic spasm with unknown reason is highly related to genetic disorders. A variety of genetic mutations, especially new mutations were found. Genetic heterogeneity of epileptic spasm is obvious.

PMID: 29141310 [PubMed - in process]

Phenotype and Management of Infantile-onset Inflammatory Bowel Disease: Experience from a Tertiary Care Center in China.

Inflamm Bowel Dis. 2017 Dec;23(12):2154-2164

Authors: Ye Z, Zhou Y, Huang Y, Wang Y, Lu J, Tang Z, Miao S, Dong K, Jiang Z

Abstract
BACKGROUND: Infantile-onset inflammatory bowel disease (IBD) comprises rare and clinically severe disorders. We examined the phenotypes and genetic causes of patients with infantile-onset IBD from a tertiary medical center.
METHODS: We enrolled 38 patients with infantile-onset IBD and applied standardized treatment with medical, surgical, and supportive care. Targeted sequencing and whole-exome sequencing were performed. Clinical data were retrieved from medical records.
RESULTS: Median age of onset of disease was 12.5 (interquartile range: 7.0-30.0) days. All patients had diarrhea, whereas 18 (47.4%) patients reported hematochezia. Thirteen (34.2%) patients had oral ulcers, 15 (39.5%) patients had perianal abscess, and 9 (52.9%) female patients had rectovaginal fistula. Six (18.8%) patients had intestinal strictures and 4 (12.1%) patients had perforation. Twelve (31.6%) patients underwent surgical procedures. Median age of surgery was 272.5 days, and cumulative probability for surgery during first year was 32.1%. One-year mortality of patients was 25.9%. Sequencing showed 24 (63.2%) patients had causative IL10RA mutations, 1 patient had EPCAM mutation, 1 patient had TNFAIP3 mutation, and 1 patient had LRBA mutation, whereas causative mutations cannot be identified in the other 11 (28.9%) patients. Umbilical cord blood stem cell transplantation has been applied to 8 cases with IL10RA mutations, of whom 5 (71.4%) patients have achieved clinical remission.
CONCLUSIONS: Patients with infantile-onset IBD had severe phenotype and early onset. Medical, surgical interventions with supportive care are essential. High-throughput sequencing ensures appropriate treatment. Hematopoietic stem cell transplantation can be performed in selected patients with IL10RA mutations (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B657).

PMID: 29140941 [PubMed - in process]