Genomics and pharmacogenomics of pediatric acute lymphoblastic leukemia.

Crit Rev Oncol Hematol. 2018 Jun;126:100-111

Authors: Wu C, Li W

Abstract
Acute lymphoblastic leukaemia (ALL) is a prevalent form of pediatric cancer that accounts for 70-80% of all leukemias. Genome-based analysis, exome sequencing, transcriptomics and proteomics have provided insight into genetic classification of ALL and helped identify novel subtypes of the disease. B and T cell-based ALL are two well-characterized genomic subtypes, significantly marked by bone marrow disorders, along with mutations in trisomy 21 and T53. The other ALLs include Early T-cell precursor ALL, Philadelphia chromosome-like ALL, Down syndrome-associated ALL and Relapsed ALL. Chromosomal number forms a basis of classification, such as, hypodiploid ALL, near-haploid, low-hypodiploid, high-hypodiploid and hypodiploid-ALL. Advances in therapies targeting ALL have been noteworthy, with significant pre-clinical and clinical studies on drug pharmacokinetics and pharmacodynamics. Methotrexate and 6-mercaptopurine are leading drugs with best demonstrated efficacies against childhood ALL. The drugs in combination, following dose titration, have also been used for maintenance therapy. Methotrexate-polyglutamate is a key metabolite that specifically targets the disease pathogenesis, and 6-thioguanine nucleotides, derived from 6-mercaptopurine, impede replication and transcription processes, inducing cytotoxicity. Additionally, glucocorticoids, asparaginase, anthracycline, vincristine and cytarabine that trans-repress gene expression, deprives cells of asparagine, triggers cell cycle arrest, influences cytochrome-P450 polymorphism and inhibits DNA polymerase, respectively, have been used in chemotherapy in ALL patients. Overall, this review covers the progress in genome technology related to different sub-types of ALL and pharmacokinetics and pharmacodynamics of its medications. It also enlightens adverse effects of current drugs, and emphasizes the necessity of genome-wide association studies for restricting childhood ALL.

PMID: 29759551 [PubMed - in process]

Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature.

Genet Med. 2017 Oct 12;:

Authors: Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, Hisado-Oliva A, Klinger P, Kraus C, Trautmann U, Zenker M, Zweier C, Wiesener A, Abou Jamra R, Kunstmann E, Wieczorek D, Uebe S, Ferrazzi F, Büttner C, Ekici AB, Rauch A, Sticht H, Dörr HG, Reis A, Thiel CT

Abstract
PurposeShort stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity.MethodsWe systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth.ResultsBy standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5% of these patients who manifested only part of the symptomatology. In 15.5% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5% of the cases.ConclusionA combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature.GENETICS in MEDICINE advance online publication, 12 October 2017; doi:10.1038/gim.2017.159.

PMID: 29758562 [PubMed - as supplied by publisher]

Filaggrin 2 deficiency results in abnormal cell-cell adhesion in the cornified cell layers and causes peeling skin syndrome type A.

J Invest Dermatol. 2018 May 11;:

Authors: Mohamad J, Sarig O, Godsel LM, Peled A, Malchin N, Bochner R, Vodo D, Rabinowitz T, Pavlovsky M, Taiber S, Fried M, Eskin-Schwartz M, Assi S, Shomron N, Uitto J, Koetsier JL, Bergman R, Green KJ, Sprecher E

Abstract
Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring non-inflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which co-segregated with the disease phenotype in the family. The mutation was found to result in decreased FLG2 RNA levels as well almost total absence of filaggrin 2 in the patient epidermis. Filaggrin 2 was found to be expressed throughout the cornified cell layers and to co-localize with corneodesmosin which plays a crucial role in maintaining cell-cell adhesion in this region of the epidermis. Absence of filaggrin 2 in the patient skin was associated with markedly decreased corneodesmosin expression, which may contribute to the peeling phenotype displayed by the patients. Accordingly, using the dispase dissociation assay, we showed that FLG2 down-regulation interferes with keratinocyte cell-cell adhesion. Of particular interest, this effect was aggravated by temperature elevation, consistent with the clinical phenotype. Restoration of CDSN levels by ectopic expression rescued cell-cell adhesion.Taken together, the present data suggest that filaggrin 2 is essential for normal cell-cell adhesion in the cornified cell layers.

PMID: 29758285 [PubMed - as supplied by publisher]

The genetic component of preeclampsia: A whole-exome sequencing study.

PLoS One. 2018;13(5):e0197217

Authors: Hansen AT, Bernth Jensen JM, Hvas AM, Christiansen M

Abstract
Preeclampsia is a major cause of maternal and perinatal deaths. The aetiology of preeclampsia is largely unknown but a polygenetic component is assumed. To explore this hypothesis, we performed an in-depth whole-exome sequencing study in women with (cases, N = 50) and without (controls, N = 50) preeclampsia. The women were identified in an unselected cohort of 2,545 pregnant women based on data from the Danish National Patient Registry and the Medical Birth Registry. Matching DNA was obtained from a biobank containing excess blood from routine antenatal care visits. Novogene performed the whole-exome sequencing blinded to preeclampsia status. Variants for comparison between cases and controls were filtered in the Ingenuity Variant Analysis software. We applied two different strategies; a disease association panel approach, which included variants in single genes associated with established clinical risk factors for preeclampsia, and a gene panel approach, which included biological pathways harbouring genes previously reported to be associated with preeclampsia. Variant variability was compared in cases and controls at the level of biological processes, signalling pathways, and in single genes. Regardless of the applied strategy and the level of variability examined, we consistently found positive correlations between variant numbers in cases and controls (all R2s>0.88). Contrary to what was expected, cases carried fewer variants in biological processes and signalling pathways than controls (all p-values ≤0.02). In conclusion, our findings challenge the hypothesis of a polygenetic aetiology for preeclampsia with a common network of susceptibility genes. The greater genetic diversity among controls may suggest a protective role of genetic diversity against the development of preeclampsia.

PMID: 29758065 [PubMed - in process]

Mutations in PPCS, Encoding Phosphopantothenoylcystein Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.

Am J Hum Genet. 2018 May 03;:

Authors: Iuso A, Wiersma M, Schüller HJ, Pode-Shakked B, Marek-Yagel D, Grigat M, Schwarzmayr T, Berutti R, Alhaddad B, Kanon B, Grzeschik NA, Okun JG, Perles Z, Salem Y, Barel O, Vardi A, Rubinshtein M, Tirosh T, Dubnov-Raz G, Messias AC, Terrile C, Barshack I, Volkov A, Avivi C, Eyal E, Mastantuono E, Kumbar M, Abudi S, Braunisch M, Strom TM, Meitinger T, Hoffmann GF, Prokisch H, Haack TB, Brundel BJJM, Haas D, Sibon OCM, Anikster Y

Abstract
Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcystein synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcystein. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

PMID: 29754768 [PubMed - as supplied by publisher]

Whole Exome Sequencing Identifies New Host Genomic Susceptibility Factors in Empyema Caused by Streptococcus pneumoniae in Children: A Pilot Study.

Genes (Basel). 2018 May 03;9(5):

Authors: Salas A, Pardo-Seco J, Barral-Arca R, Cebey-López M, Gómez-Carballa A, Rivero-Calle I, Pischedda S, Currás-Tuala MJ, Amigo J, Gómez-Rial J, Martinón-Torres F, GENDRES Network

Abstract
Pneumonia is the leading cause of death amongst infectious diseases. Streptococcus pneumoniae is responsible for about 25% of pneumonia cases worldwide, and it is a major cause of childhood mortality. We carried out a whole exome sequencing (WES) study in eight patients with complicated cases of pneumococcal pneumonia (empyema). An initial assessment of statistical association of WES variation with pneumonia was carried out using data from the 1000 Genomes Project (1000G) for the Iberian Peninsula (IBS) as reference controls. Pseudo-replication statistical analyses were carried out using different European control groups. Association tests pointed to single nucleotide polymorphism (SNP) rs201967957 (gene MEIS1; chromosome 2; p-valueIBS = 3.71 × 10-13) and rs576099063 (gene TSPAN15; chromosome 10; p-valueIBS = 2.36 × 10-8) as the best candidate variants associated to pneumococcal pneumonia. A burden gene test of pathogenicity signaled four genes, namely, OR9G9, MUC6, MUC3A and APOB, which carry significantly increased pathogenic variation when compared to controls. By analyzing various transcriptomic data repositories, we found strong supportive evidence for the role of MEIS1, TSPAN15 and APOBR (encoding the receptor of the APOB protein) in pneumonia in mouse and human models. Furthermore, the association of the olfactory receptor gene OR9G9 has recently been related to some viral infectious diseases, while the role of mucin genes (MUC6 and MUC3A), encoding mucin glycoproteins, are well-known factors related to chronic obstructive airway disease. WES emerges as a promising technique to disentangle the genetic basis of host genome susceptibility to infectious respiratory diseases.

PMID: 29751582 [PubMed]

Forkhead box C1 gene variant causing glaucoma and small vessel angiopathy can mimic multiple sclerosis.

Mult Scler Relat Disord. 2018 Apr 21;22:157-160

Authors: Avasarala JR, Jones JR, Rogers CR

Abstract
A 34-year old Caucasian female was initially diagnosed with multiple small-vessel strokes at age 20 years which were etiologically classified as secondary to anti-phospholipid antibody syndrome (APS) although she had no history or laboratory data to suggest APS. Based on her MRI of brain findings, one of her neurologists was concerned she could have multiple sclerosis (MS) and hence the patient was referred to our clinic for further evaluation. The patient's MRI of brain showed confluent lesions in the periventricular and juxta-cortical lesions that fulfil 2017 McDonald criteria for dissemination in space. She had no symptoms other than occasional, mild headaches and had no findings to suggest clinically isolated syndrome (CIS) or MS; additionally, her cerebrospinal fluid analysis was unremarkable. Past history showed that she had undergone surgery for glaucoma, and subsequently developed bilateral sensorineural hearing loss in the third decade that was diagnosed as Meniere's disease. Her family history revealed that her son had dysmorphic facies and was small for age. He had a bifid uvula, bilaterally duplicated thumbs and scoliosis. Additionally, he had hypertelorism, a wide forehead and flattening of mid-face. Due to his complex medical presentation, whole exome sequencing (WES) was performed that revealed a maternally inherited heterozygous pathogenic frameshift in the FOXC1 gene. Genotyping of the mother showed the FOXC1 gene variant and adds to the growing list of differential diagnoses that may mimic MS in the context of radiological changes involving cerebral small vessels. This is the first report of a FOXC1 gene variant presenting with radiological features that can erroneously be interpreted as being consistent with MS.

PMID: 29751260 [PubMed - as supplied by publisher]

Whole Exome Sequencing of an Exceptional Longevity Cohort.

J Gerontol A Biol Sci Med Sci. 2018 May 10;:

Authors: Nygaard HB, Erson-Omay EZ, Wu X, Kent BA, Bernales CQ, Evans DM, Farrer MJ, Vilariño-Güell C, Strittmatter SM

Abstract
Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and supercententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not fully characterized. To address these questions, we performed whole exome sequencing on 100 individuals of 98-108 years age in search of genes with large effect sizes towards the exceptional aging phenotype. Overall, we were unable to identify a rare protein-altering variant or individual genes with an increased burden of rare variants associated with exceptional longevity. Gene burden analysis revealed three genes of nominal statistical significance associated with extreme aging, including LYST, MDN1, and RBMXL1. Several genes with variants conferring an increased risk for AD and other dementias were identified, including TREM2, EPHA1, ABCA7, PLD3, MAPT, and NOTCH3. Larger centenarian studies will be required to further elucidate the genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.

PMID: 29750252 [PubMed - as supplied by publisher]

Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement.

Neurobiol Aging. 2018 Apr 16;:

Authors: Ng AS, Tan YJ, Yi Z, Tandiono M, Chew E, Dominguez J, Macas M, Ng E, Hameed S, Ting S, Tan EK, Foo JN, Kandiah N

Abstract
To identify genes associated with frontotemporal dementia (FTD) in South-East Asia, targeted exome sequencing and C9orf72 genotyping was performed in 198 subjects (52 patients with FTD and 146 healthy controls) who were screened for mutations in 12 FTD-associated genes. We detected a homozygous TREM2 R47C mutation in a patient with behavioral variant FTD without bone cysts or bone-associated phenotype. Two novel nonsense GRN mutations in 3 FTD patients from the Philippines were detected, but no known pathogenic mutations in other FTD-associated genes were found. In 45 subjects screened for C9orf72 repeat expansions, no pathogenic expansion (≥30 repeats) was identified, but there was a higher proportion of intermediate length (≥10-29 repeats) alleles in patients compared with controls (8/90 alleles, 8.9% vs. 9/164 alleles, 5.5%). Overall, we detected a mutation rate of 7.7% (4/52 patients) in our cohort. Given recent findings of enrichment of rare TREM2 variants (including R47C) in Alzheimer's disease, it is notable that we detected a homozygous TREM2 R47C carrier presenting with an FTD rather than an Alzheimer's disease phenotype.

PMID: 29748150 [PubMed - as supplied by publisher]

Identification of the PROM1 Mutation p.R373C in a Korean Patient With Autosomal Dominant Stargardt-like Macular Dystrophy.

Ann Lab Med. 2017 Nov;37(6):536-539

Authors: Kim JM, Lee C, Lee GI, Kim NKD, Ki CS, Park WY, Kim BJ, Kim SJ

Abstract
Stargardt-like macular dystrophy 4 (STGD4) is a rare macular dystrophy characterized by bull's eye atrophy of the macula and the underlying retinal pigment epithelium. Patients with STGD4 show decreased central vision, which often progresses to severe vision loss. The PROM1 gene encodes prominin-1, which is a 5-transmembrane glycoprotein also known as CD133 and is involved in photoreceptor disk morphogenesis. PROM1 mutations have been identified as genetic causes for STGD4 and other retinal degenerations such as retinitis pigmentosa. We report a case of STGD4 with a PROM1 p.R373C mutation in a Korean patient. Ophthalmic examinations of a 38-yr old man complaining of decreased visual acuity revealed bilateral atrophic macular lesions consistent with STGD4. Targeted exome sequencing of known inherited retinal degeneration genes revealed a heterozygous missense mutation c.1117C>T (p.R373C) of PROM1, which was confirmed by Sanger sequencing. To the best of our knowledge, this is the first case of a PROM1 mutation causing STGD4 in Koreans.

PMID: 28840994 [PubMed - indexed for MEDLINE]

Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer.

DNA Repair (Amst). 2018 Apr 26;66-67:50-63

Authors: Das R, Kundu S, Laskar S, Choudhury Y, Ghosh SK

Abstract
Head and neck cancer (HNC), the sixth most common cancer globally, stands second in India. In Northeast (NE) India, it is the sixth most common cause of death in males and seventh in females. Prolonged tobacco and alcohol consumption constitute the major etiological factors for HNC development, which induce DNA damage. Therefore, DNA repair pathway is a crucial system in maintaining genomic integrity and preventing carcinogenesis. The present work was aimed to predict the consequence of significant germline variants of the DNA repair genes in disease predisposition. Whole exome sequencing was performed in Ion Proton™ platform on 15 case-control samples from the HNC-prevalent states of Manipur, Mizoram, and Nagaland. Variant annotation was done in Ion Reporter™ as well as wANNOVAR. Subsequent statistical and bioinformatics analysis identified significant exonic and intronic variants associated with HNC. Amongst our observed variants, 78.6% occurred in ExAC, 94% reported in dbSNP and 5.8% & 9.3% variants were present in ClinVar and HGMD, respectively. The total variants were dispersed among 199 genes with DSBR and FA pathway being the most mutated pathways. The allelic association test suggested that the intronic variants in HLTF and RAD52 gene significantly associated (P < 0.05) with the risk (OR > 5), while intronic variants in PARP4, RECQL5, EXO1 and PER1 genes and exonic variant in TDP2 gene showed protection (OR < 1) for HNC. MDR analysis proposed the exonic variants in MSH6, BRCA2, PALB2 and TP53 genes and intronic variant in RECQL5 genetic region working together during certain phase of DNA repair mechanism for HNC causation. In addition, other intronic and 3'UTR variations caused modifications in the transcription factor binding sites and miRNA target sites associated with HNC. Large-scale validation in NE Indian population, in-depth structure prediction and subsequent simulation of our recognized polymorphisms is necessary to identify true causal variants related to HNC.

PMID: 29747023 [PubMed - as supplied by publisher]

Widespread and debilitating hemangiomas in a patient with enchondromatosis and D-2-hydroxyglutaric aciduria.

Skeletal Radiol. 2018 May 10;:

Authors: Yeetong P, Phewplung T, Kamolvisit W, Suphapeetiporn K, Shotelersuk V

Abstract
Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) (OMIM 614875) is a severe chondrodysplasia combined with a urinary excretion of D-2-hydroxyglutaric acid. Here, we reported the tenth case of this disease. A 15-year-old boy had symmetric radiolulencies in the metaphyses of the long bones suggesting enchondromatosis and platyspondyly. Remarkably, he manifested widespread cavernous hemangiomas including scalp, lips, tongue, larynx, and prepuce, with the onset of 3 years of age. Hemangiomas at the larynx had caused dyspnea and those in the oral cavity led to recurrent bleeding, requiring several surgical removals. These multiple and debilitating hemangiomas have never been previously reported in patients with MC-HGA. Mutation analyses including Sanger sequencing of genes involving in enchondromatosis and the metabolic pathway of D-2-hydroxyglutarate including PTHR1, D2HGDH, HOT, and IDH1, as well as whole-exome sequencing for proband-parent trio analysis and paired blood versus hemangioma studies showed no pathogenic variants. In summary, we reported the tenth patient with MC-HGA who manifested widespread and debilitating hemangiomas in several organs, expanding the clinical spectrum of MC-HGA.

PMID: 29744569 [PubMed - as supplied by publisher]

TDRD6 is associated with oligoasthenoteratozoospermia by sequencing the patient from a consanguineous family.

Gene. 2018 Jun 15;659:84-88

Authors: Sha YW, Wang X, Su ZY, Wang C, Ji ZY, Mei LB, Zhang L, Deng BB, Huang XJ, Yan W, Chen J, Li P, Cui YQ, Qu QL, Yin C, He XM

Abstract
Oligoasthenoteratozoospermia (OAT) is characterized as low sperm count, decreased sperm motility and structural abnormalities of the sperm head in the same patient. However, very few studies reported the genetic alterations associated with OAT. Here we report a 38-year-old patient with OAT from a consanguineous family, with 2-6 million/mL sperm density, 2.1-3.8% normal sperm morphology and immotile sperm. Whole-exome sequencing (WES) identified homozygous variant c.1259A>G:p.Y420C in the TDRD6 gene. TDRD6 is a testis-specific expressed protein that was localized to the chromatoid bodies in germ cells and played an important role in the nonsense-mediated decay pathway. This rare variant co-segregated with the OAT phenotype in this family. Bioinformatic analysis also suggested the variant a pathogenic mutation. Two intracytoplasmic sperm injection (ICSI) cycles were carried out in the patient's wife, but she did not become pregnant after embryo transfer. So the mutations in TDRD6 may be associated with human male infertility and early embryonic lethality.

PMID: 29551503 [PubMed - indexed for MEDLINE]

New role of LRP5, associated with nonsyndromic autosomal-recessive hereditary hearing loss.

Hum Mutat. 2017 Oct;38(10):1421-1431

Authors: Xia W, Hu J, Liu F, Ma J, Sun S, Zhang J, Jin K, Huang J, Jiang N, Wang X, Li W, Ma Z, Ma D

Abstract
Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. At least 50% of hearing loss are due to a genetic etiology. Although hundreds of genes have been reported, there are still hundreds of related deafness genes to be found. Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual nonsyndromic sensorineural hearing loss. Whole-exome sequencing (WES) identified lipoprotein receptor-related protein 5 (LRP5), a member of the low-density lipoprotein receptor family, as the causative gene in this family. In the zebrafish model, lrp5 downregulation using morpholinos led to significant abnormalities in zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. Rescue experiments showed that LRP5 mutation is associated with hearing loss. Knocking down lrp5 in zebrafish results in reduced expression of several genes linked to Wnt signaling pathway and decreased cell proliferation when compared with those in wild-type zebrafish. In conclusion, the LRP5 mutation influences cell proliferation through the Wnt signaling pathway, thereby reducing the number of supporting cells and hair cells and leading to nonsyndromic hearing loss in this Chinese family.

PMID: 28677207 [PubMed - indexed for MEDLINE]

A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita.

Medicine (Baltimore). 2018 May;97(19):e0724

Authors: Du H, Guo Y, Ma D, Tang K, Cai D, Luo Y, Xie C

Abstract
RATIONALE: Dyskeratosis congenita (DC) is a rare inherited disease characterized by the classical mucocutaneous triad. Pulmonary fibrosis, bone marrow failure, and solid tumors are the main causes of mortality in DC. Pathogenic variants in TERT, TERC, and DKC1 have been identified in individuals with familial pulmonary fibrosis. Mutations in TINF2 gene have been reported to be associated with bone marrow failure in most cases. However, the relationship between TINF2 mutation and pulmonary fibrosis is not yet clear.
PATIENT CONCERNS: Here, we report the case of a 32-year-old woman presented with irritating cough for 2 years and progressive breathlessness for 6 months.
DIAGNOSES: The patient was diagnosed with DC based on the following clinical evidences. Along with some family members, she had the typical mucocutaneous triad and pulmonary fibrosis. A heterozygous mutation (c.844C>T), located in exon 6 of TINF2 gene, that changed arginine to cysteine (Arg282Cys) was identified in this proband by whole exome sequencing.
INTERVENTIONS: The patient received corticosteroid therapy but refused to receive lung transplantation.
OUTCOMES: The proband died of respiratory failure 4 months after the diagnosis. The missense mutation was located in the conserved region of TINF2 gene and predicted to be deleterious by altering the protein structure.
LESSONS: Lung transplantation should be considered for improved survival of patients with DC, and pulmonary fibrosis. Whole exome and whole genome sequencing should be widely used in the identification of such rare genetic variants for clinical diagnosis. The study of DC with pulmonary fibrosis can provide a more appropriate means of clinical research and therapy to the unfortunate patients who suffer from this rare disorder.

PMID: 29742735 [PubMed - in process]

Gain-of-function mutations in DNMT3A in patients with paraganglioma.

Genet Med. 2018 May 08;:

Authors: Remacha L, Currás-Freixes M, Torres-Ruiz R, Schiavi F, Torres-Pérez R, Calsina B, Letón R, Comino-Méndez I, Roldán-Romero JM, Montero-Conde C, Santos M, Pérez LI, Pita G, Alonso MR, Honrado E, Pedrinaci S, Crespo-Facorro B, Percesepe A, Falcioni M, Rodríguez-Perales S, Korpershoek E, Ramón-Maiques S, Opocher G, Rodríguez-Antona C, Robledo M, Cascón A

Abstract
PURPOSE: The high percentage of patients carrying germline mutations makes pheochromocytomas/paragangliomas the most heritable of all tumors. However, there are still cases unexplained by mutations in the known genes. We aimed to identify the genetic cause of disease in patients strongly suspected of having hereditary tumors.
METHODS: Whole-exome sequencing was applied to the germlines of a parent-proband trio. Genome-wide methylome analysis, RNA-seq, CRISPR/Cas9 gene editing, and targeted sequencing were also performed.
RESULTS: We identified a novel de novo germline mutation in DNMT3A, affecting a highly conserved residue located close to the aromatic cage that binds to trimethylated histone H3. DNMT3A-mutated tumors exhibited significant hypermethylation of homeobox-containing genes, suggesting an activating role of the mutation. CRISPR/Cas9-mediated knock-in in HeLa cells led to global changes in methylation, providing evidence of the DNMT3A-altered function. Targeted sequencing revealed subclonal somatic mutations in six additional paragangliomas. Finally, a second germline DNMT3A mutation, also causing global tumor DNA hypermethylation, was found in a patient with a family history of pheochromocytoma.
CONCLUSION: Our findings suggest that DNMT3A may be a susceptibility gene for paragangliomas and, if confirmed in future studies, would represent the first example of gain-of-function mutations affecting a DNA methyltransferase gene involved in cancer predisposition.

PMID: 29740169 [PubMed - as supplied by publisher]

Exome sequencing revealed C1Q homozygous mutation in Pediatric Systemic Lupus Erythematosus.

Allergol Immunopathol (Madr). 2018 May 05;:

Authors: Zoghi S, Ziaee V, Hirschmugl T, Jimenez-Heredia R, Krolo A, Boztug K, Rezaei N

Abstract
INTRODUCTION AND OBJECTIVES: Pediatric Systemic Lupus Erythematosus (pSLE) is an autoimmune disorder of children. Early disease onset raises the probability of genetic etiology and it is more severe than adult SLE.
PATIENTS AND METHODS: Herein an eight-year-old girl with pSLE from consanguineous parents is reported.
RESULTS: Although she was diagnosed as pSLE since the age of two years, Whole Exome Sequencing (WES) revealed a rare stop-gained C>T mutation in C1QA gene. The variant was validated and segregated in patient and the family. Furthermore, serum levels of the C1q protein were measured and found to be much lower than normal ranges.
CONCLUSIONS: This study indicated that C1Q deficiency should be considered as a differential diagnosis of pSLE. Therefore, measurement of C1q should be recommended in all cases with pSLE.

PMID: 29739689 [PubMed - as supplied by publisher]

Case report of a novel homozygous splice site mutation in PLA2G6 gene causing infantile neuroaxonal dystrophy in a Sudanese family.

BMC Med Genet. 2018 May 08;19(1):72

Authors: Elsayed LEO, Mohammed IN, Hamed AAA, Elseed MA, Salih MAM, Yahia A, Siddig RA, Amin M, Koko M, Elbashir MI, Ibrahim ME, Brice A, Ahmed AE, Stevanin G

Abstract
BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a rare hereditary neurological disorder caused by mutations in PLA2G6. The disease commonly affects children below 3 years of age and presents with delay in motor skills, optic atrophy and progressive spastic tetraparesis. Studies of INAD in Africa are extremely rare, and genetic studies from Sub Saharan Africa are almost non-existent.
CASE PRESENTATION: Two Sudanese siblings presented, at ages 18 and 24 months, with regression in both motor milestones and speech development and hyper-reflexia. Brain MRI showed bilateral and symmetrical T2/FLAIR hyperintense signal changes in periventricular areas and basal ganglia and mild cerebellar atrophy. Whole exome sequencing with confirmatory Sanger sequencing were performed for the two patients and healthy family members. A novel variant (NM_003560.2 c.1427 + 2 T > C) acting on a splice donor site and predicted to lead to skipping of exon 10 was found in PLA2G6. It was found in a homozygous state in the two patients and homozygous reference or heterozygous in five healthy family members.
CONCLUSION: This variant has one very strong (loss of function mutation) and three supporting evidences for its pathogenicity (segregation with the disease, multiple computational evidence and specific patients' phenotype). Therefore this variant can be currently annotated as "pathogenic". This is the first study to report mutations in PLA2G6 gene in patients from Sudan.

PMID: 29739362 [PubMed - in process]

Clinical genetics of craniosynostosis.

Curr Opin Pediatr. 2017 12;29(6):622-628

Authors: Wilkie AOM, Johnson D, Wall SA

Abstract
PURPOSE OF REVIEW: When providing accurate clinical diagnosis and genetic counseling in craniosynostosis, the challenge is heightened by knowledge that etiology in any individual case may be entirely genetic, entirely environmental, or anything in between. This review will scope out how recent genetic discoveries from next-generation sequencing have impacted on the clinical genetic evaluation of craniosynostosis.
RECENT FINDINGS: Survey of a 13-year birth cohort of patients treated at a single craniofacial unit demonstrates that a genetic cause of craniosynostosis can be identified in one quarter of cases. The substantial contributions of mutations in two genes, TCF12 and ERF, is confirmed. Important recent discoveries are mutations of CDC45 and SMO in specific craniosynostosis syndromes, and of SMAD6 in nonsyndromic midline synostosis. The added value of exome or whole genome sequencing in the diagnosis of difficult cases is highlighted.
SUMMARY: Strategies to optimize clinical genetic diagnostic pathways by combining both targeted and next-generation sequencing are discussed. In addition to improved genetic counseling, recent discoveries spotlight the important roles of signaling through the bone morphogenetic protein and hedgehog pathways in cranial suture biogenesis, as well as a key requirement for adequate cell division in suture maintenance.

PMID: 28914635 [PubMed - indexed for MEDLINE]

Epithelioid Trophoblastic Tumor Around an Abdominal Cesarean Scar: A Pathologic and Molecular Genetic Analysis.

Int J Gynecol Pathol. 2017 Nov;36(6):562-567

Authors: Hsiue EH, Hsu C, Tseng LH, Lu TP, Kuo KT

Abstract
Epithelioid trophoblastic tumor (ETT) is a rare chemoresistant gestational trophoblastic neoplasm that typically presents as an intrauterine lesion. To our knowledge, no isolated abdominal wall ETT around a Cesarean scar has been reported. Here we describe a 54-yr-old woman with a complex obstetric history who presented with a solitary abdominal wall tumor adjacent to the abdominal Cesarean section scar. The tumor demonstrated typical morphologic and immunophenotypic features of ETT. The gestational origin of the tumor was confirmed by microsatellite genotyping. The tumor enlarged despite the patient undergoing multiagent chemotherapy. Whole-exome sequencing was performed to explore the mechanisms underlying chemoresistance. The ATP-binding cassette subfamily B member 1 (ABCB1) 3435CC genotype, and a putative deleterious x-ray cross-complementing group 4 (XRCC4) Ala73Pro mutations were found. In conclusion, ETT may present as a solitary abdominal wall lesion and microsatellite genotyping could facilitate the determination of its gestational origin. More studies are required to provide mechanistic insights into the chemoresistance of ETT.

PMID: 28134666 [PubMed - indexed for MEDLINE]