Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma.

J Exp Clin Cancer Res. 2018 Sep 20;37(1):233

Authors: Hsu CL, Lui KW, Chi LM, Kuo YC, Chao YK, Yeh CN, Lee LY, Huang Y, Lin TL, Huang MY, Lai YR, Yeh YM, Fan HC, Lin AC, Lu YJ, Hsieh CH, Chang KP, Tsang NM, Wang HM, Chang AY, Chang YS, Li HP

Abstract
BACKGROUND: Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets.
METHODS: We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs.
RESULTS: A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients' plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer.
CONCLUSIONS: Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.

PMID: 30236142 [PubMed - in process]

Epileptic spasms in PPP1CB-associated Noonan-like syndrome: a case report with clinical and therapeutic implications.

BMC Neurol. 2018 Sep 20;18(1):150

Authors: Lin CH, Lin WD, Chou IC, Lee IC, Fan HC, Hong SY

Abstract
BACKGROUND: Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2) is an extremely rare disease caused by a heterozygous mutation in the PPP1CB gene on chromosome 2p23. The syndrome causes not only numerous dysmorphic features but also hypotonia, developmental delay, and even intellectual disability. We report the first case of NSLH2 in Asia and the 16th in the world. Moreover, the first case of PPP1CB-related infantile spasms. The clinical and therapeutic significance is outlined in this paper.
CASE PRESENTATION: We found a male infant presented with severe intractable epileptic spasms. Although certain clinical features of somatic dysmorphism were noted, numerous laboratory and neuroimaging studies failed to identify the cause. To determine the underlying etiology, whole-exome sequencing was conducted. We identified a de novo heterozygous mutation, NM_206876.1: c.548A > C (p.Glu183Ala), in the PPP1CB gene. His seizures were almost refractory to conventional antiepileptic drugs but relative seizure control was eventually achieved with a ketogenic diet.
CONCLUSION: This result expands the clinical spectrum of NSLH2 and strengthens the association between the PPP1CB gene and epileptic seizures. Furthermore, we suggest that the ketogenic diet can offer seizure reduction in particular drug-resistant epilepsy syndromes. Additional studies are warranted to clarify the pathogenic mechanisms underlying this PPP1CB mutation in epileptic seizures.

PMID: 30236064 [PubMed - in process]

A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs.

PLoS One. 2018;13(9):e0204073

Authors: Dillard KJ, Hytönen MK, Fischer D, Tanhuanpää K, Lehti MS, Vainio-Siukola K, Sironen A, Anttila M

Abstract
Ciliopathies presenting as inherited hepatorenal fibrocystic disorders are rare in humans and in dogs. We describe here a novel lethal ciliopathy in Norwich Terrier puppies that was diagnosed at necropsy and characterized as diffuse cystic renal disease and hepatic fibrosis. The histopathological findings were typical for cystic renal dysplasia in which the cysts were located in the straight portion of the proximal tubule, and thin descending and ascending limbs of Henle's loop. The pedigree of the affected puppies was suggestive of an autosomal recessive inheritance and therefore, whole exome sequencing and homozygosity mapping were used for identification of the causative variant. The analyses revealed a case-specific homozygous splice donor site variant in a cilia related gene, INPP5E: c.1572+5G>A. Association of the variant with the defect was validated in a large cohort of Norwich Terriers with 3 cases and 480 controls, the carrier frequency being 6%. We observed that the identified variant introduces a novel splice site in INPP5E causing a frameshift and formation of a premature stop codon. In conclusion, our results suggest that the INPP5E: c.1572+5G>A variant is causal for the ciliopathy in Norwich Terriers. Therefore, genetic testing can be carried out in the future for the eradication of the disease from the breed.

PMID: 30235266 [PubMed - in process]

Genetic Testing of a Large Consanguineous Pakistani Family Affected with Mucolipidosis III Gamma Through Next-Generation Sequencing.

Genet Test Mol Biomarkers. 2018 Sep;22(9):541-545

Authors: Khan MA, Hussain A, Sher G, Zubaida B, Naeem M

Abstract
BACKGROUND: Mucolipidosis III gamma (MLIIIγ) is a rare autosomal recessive disorder characterized by radiographic evidence of mild-to-moderate dysostosis multiplex, progressive joint stiffness and pain, scoliosis, and normal to mildly impaired cognitive development. Cardiac valve involvement and respiratory complications can be significant. MLIIIγ is caused by mutations in the GNPTG, which encodes the γ subunit of the enzyme N-acetylglucosamine-1-phosphotransferase.
OBJECTIVE: Clinical and genetic study of seven individuals of a consanguineous Pakistani family affected with mucolipidosis phenotype who never pursued medical care.
METHODS: Genome-wide homozygosity mapping was performed using Affymetrix Human SNP Array 6.0 followed by whole exome and Sanger sequencing.
RESULTS: The affected individuals showed characteristic clinical features of MLIIIγ. Whole-genome single nucleotide polymorphism genotyping identified a region of homozygosity shared by affected individuals of the family on chromosome 16p13.3. Whole exome sequencing identified a novel 4-bp deletion in the GNPTG segregating in the family in agreement with autosomal recessive pattern.
CONCLUSIONS: We identified a novel mutation in the GNPTG gene as the underlying cause of MLIIIγ in a Pakistani family. This study supports the role of next-generation sequencing technologies for the molecular diagnosis of rare inherited disorders.

PMID: 30235039 [PubMed - in process]

A phase II trial of the aurora kinase A inhibitor alisertib for patients with castration resistant and neuroendocrine prostate cancer: efficacy and biomarkers.

Clin Cancer Res. 2018 Sep 19;:

Authors: Beltran H, Oromendia C, Danila DC, Montgomery B, Hoimes C, Szmulewitz RZ, Vaishampayan U, Armstrong AJ, Stein M, Pinski J, Mosquera JM, Sailer V, Bareja R, Romanel A, Gumpeni N, Sboner A, Dardenne E, Puca L, Prandi D, Rubin MA, Scher HI, Rickman DS, Demichelis F, Nanus DM, Ballman KV, Tagawa ST

Abstract
BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth.
EXPERIMENTAL DESIGN: Sixty men were treated with alisertib50mg twice daily for 7 days every 21-days. Eligibility included metastatic prostate cancer and at least one: small cell neuroendocrine morphology; 50% neuroendocrine marker expression; new liver metastases without PSA progression; elevated serum neuroendocrine markers. The primary endpoint was six-month radiographic progression free survival (rPFS). Pre-treatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed.
RESULTS: Median PSA was 1.13 ng/ml (0.01-514.2), number of prior therapies was three, and 68% had visceral metastases. Genomic alterations involved RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%),AR (27%), and there was a range of androgen receptor signaling and NEPC marker expression. Six-month rPFS was 13.4% and median overall survival was 9.5 months (7.3-13). Four exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity. Patient organoids exhibited concordant responses to alisertib and allowed for the dynamic testing of Aurora-N-myc complex disruption.
CONCLUSIONS: Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.

PMID: 30232224 [PubMed - as supplied by publisher]

Genetic analysis of resistance to stripe rust in durum wheat (Triticum turgidum L. var. durum).

PLoS One. 2018;13(9):e0203283

Authors: Lin X, N'Diaye A, Walkowiak S, Nilsen KT, Cory AT, Haile J, Kutcher HR, Ammar K, Loladze A, Huerta-Espino J, Clarke JM, Ruan Y, Knox R, Fobert P, Sharpe AG, Pozniak CJ

Abstract
Stripe rust, caused by the fungal pathogen Puccinia striiformis Westend. f. sp. tritici Eriks, is an important disease of bread wheat (Triticum aestivum L.) worldwide and there is an indication that it may also become a serious disease of durum wheat (T. turgidum L. var. durum). Therefore, we investigated the genetic architecture underlying resistance to stripe rust in adapted durum wheat germplasm. Wheat infection assays were conducted under controlled conditions in Canada and under field conditions in Mexico. Disease assessments were performed on a population of 155 doubled haploid (DH) lines derived from the cross of Kofa (susceptible) and W9262-260D3 (moderately resistant) and on a breeding panel that consisted of 92 diverse cultivars and breeding lines. Both populations were genotyped using the 90K single-nucleotide polymorphism (SNP) iSelect assay. In the DH population, QTL for stripe rust resistance were identified on chromosome 7B (LOD 6.87-11.47) and chromosome 5B (LOD 3.88-9.17). The QTL for stripe rust resistance on chromosome 7B was supported in the breeding panel. Both QTL were anchored to the genome sequence of wild emmer wheat, which identified gene candidates involved in disease resistance. Exome capture sequencing identified variation in the candidate genes between Kofa and W9262-260D3. These genetic insights will be useful in durum breeding to enhance resistance to stripe rust.

PMID: 30231049 [PubMed - in process]

Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype.

Liver Int. 2018 Sep 19;:

Authors: Kluska A, Kulecka M, Litwin T, Dziezyc K, Balabas A, Piatkowska M, Paziewska A, Dabrowska M, Mikula M, Kaminska D, Wiernicka A, Socha P, Czlonkowska A, Ostrowski J

Abstract
BACKGROUND & AIMS: Wilson's disease (WD) is an autosomal recessive disorder associated with disease-causing alterations across the ATP7B gene, with highly variable symptoms and age of onset. We aimed to assess whether the clinical variability of WD relates to modifier genes.
METHODS: 248 WD patients were included, of whom 148 were diagnosed after age of 17. Human exome libraries were constructed using AmpliSeq technology and sequenced using the IonProton platform.
RESULTS: ATP7B p.His1069Gln mutation was present in 215 patients, with 112 homozygotes and 103 heterozygotes. Three other mutations: p.Gln1351Ter, p.Trp779Ter, and c.3402delC were identified in >10 patients. Among patients, 117 had a homozygous mutation, 101 were compound heterozygotes, 27 had one heterozygous mutation, and 3 other patients had no identifiable pathogenic variant of ATP7B. Sixteen mutations were novel, found as part of a compound mutation or as a sole, homozygous mutation. For disease phenotype prediction, age at diagnosis was a deciding factor, while frameshift allelic variants of ATP7B and being male increased the odds of developing a neurological phenotype. Rare allelic variants in ESD and INO80 increased and decreased chances for the neurologic phenotype, respectively, while rare variants in APOE and MBD6 decreased the chances of WD early manifestation. Compound mutations contributed to earlier age of onset.
CONCLUSIONS: In a Polish population, genetic screening for WD may help genotype for four variants (p.His1069Gln, p.Gln1351Ter, p.Trp779Ter, c.3402delC), with direct sequencing of all ATP7B amplicons as a second diagnostic step. We also identified some allelic variants that may modify a WD phenotype. This article is protected by copyright. All rights reserved.

PMID: 30230192 [PubMed - as supplied by publisher]

Immune receptor recombinations from breast cancer exome files, independently and in combination with specific HLA alleles, correlate with better survival rates.

Breast Cancer Res Treat. 2018 Sep 18;:

Authors: Tong WL, Callahan BM, Tu YN, Zaman S, Chobrutskiy BI, Blanck G

Abstract
PURPOSE: Immune characterizations of cancers, including breast cancer, have led to information useful for prognoses and are considered to be important in the future of refining the use of immunotherapies, including immune checkpoint inhibitor therapies. In this study, we sought to extend these characterizations with genomics approaches, particularly with cost-effective employment of exome files.
METHODS: By recovery of immune receptor recombination reads from the cancer genome atlas (TCGA) breast cancer dataset, we observed associations of these recombinations with T-cell and B-cell biomarkers and with distinct survival rates.
RESULTS: Recovery of TRD or IGH recombination reads was associated with an improved disease-free survival (p = 0.047 and 0.045, respectively). Determination of the HLA types using the exome files allowed matching of T-cell receptor V- and J-gene segment usage with specific HLA alleles, in turn allowing a refinement of the association of immune receptor recombination read recoveries with survival. For example, the TRBV7, HLA-C*07:01 combination represented a significantly worse, disease-free outcome (p = 0.014) compared to all other breast cancer samples. By direct comparisons of distinct TRB gene segment usage, HLA allele combinations revealed breast cancer subgroups, within the entire TCGA breast cancer dataset with even more dramatic survival distinctions.
CONCLUSIONS: In sum, the use of exome files for recovery of adaptive immune receptor recombination reads, and the simultaneous determination of HLA types, has the potential of advancing the use of immunogenomics for immune characterization of breast tumor samples.

PMID: 30229447 [PubMed - as supplied by publisher]

Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis.

Int J Cardiol. 2018 Sep 13;:

Authors: Hayano S, Okuno Y, Tsutsumi M, Inagaki H, Fukasawa Y, Kurahashi H, Kojima S, Takahashi Y, Kato T

Abstract
BACKGROUND: Supravalvular aortic stenosis (SVAS) is a congenital heart disease affecting approximately 1:25,000 live births. SVAS may occur sporadically, be inherited in an autosomal dominant manner, or be associated with Williams-Beuren syndrome, a complex developmental disorder caused by a microdeletion of chromosome 7q11.23. ELN on 7q11.23, which encodes elastin, is the only known gene to be recurrently mutated in less than half of SVAS patients.
METHODS: Whole-exome sequencing (WES) was performed for seven familial SVAS families to identify other causative gene mutations of SVAS.
RESULTS: Three truncating mutations and three intragenic deletions affecting ELN were identified, yielding a diagnostic efficiency of 6/7 (85%). The deletions, which explained 3/7 of the present cohort, spanned 1-29 exons, which might be missed in the course of mutational analysis targeting point mutations. The presence of such deletions was validated by both WES-based copy number estimation and multiplex ligation-dependent probe amplification analyses, and their pathogenicity was reinforced by co-segregation with clinical presentations.
CONCLUSIONS: The majority of familial SVAS patients appear to carry ELN mutations, which strongly indicates that elastin is the most important causative gene for SVAS. The frequency of intragenic deletions highlights the need for quantitative tests to analyze ELN for efficient genetic diagnosis of SVAS.

PMID: 30228022 [PubMed - as supplied by publisher]

Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer.

Int J Cancer. 2018 03 01;142(5):927-939

Authors: Di J, Yang H, Jiang B, Wang Z, Ji J, Su X

Abstract
Sporadic synchronous colorectal cancer (CRC) refers to more than one primary tumor detected in a single patient at the time of the first diagnosis without predisposition of cancer development. Given the same genetic and microenvironment they raise, sporadic synchronous CRC is a unique model to study CRC tumorigenesis. We performed whole exome sequencing in 32 fresh frozen tumor lesions from 15 patients with sporadic synchronous CRC to compare their genetic alterations. This approach identified ubiquitously mutated genes in the range from 0.34% to 4.22% and from 0.8% to 7.0% in non-hypermutated tumors and hypermutated tumors, respectively, in a single patient. We show that both ubiquitously mutated genes and candidate cancer genes from different tumors in the same patient mutated at different sites. Consistently, obvious differences in somatic copy number variations (SCNV) were found in most patients with non-hypermutated tumor lesions, which had ubiquitous copy number amplification rates ranging from 0% to 8.8% and ubiquitous copy number deletion rates ranging from 0% to 8.2%. Hypermutated lesions were nearly diploid with 0% to 18.8% common copy number aberrations. Accordingly, clonal structures, altered signaling pathways and druggable genes in a single patient with synchronous CRC varied significantly. Taken together, the disparate SCNVs and mutations in synchronous CRC supported the field effect theory of tumorigenesis. Moreover, the intertumor heterogeneity of synchronous CRCs implies that analysis of all tumor lesions from the same patient is necessary for appropriate clinical treatment decisions.

PMID: 29105743 [PubMed - indexed for MEDLINE]

Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer.

Nat Commun. 2018 Sep 17;9(1):3787

Authors: Wagner AH, Devarakonda S, Skidmore ZL, Krysiak K, Ramu A, Trani L, Kunisaki J, Masood A, Waqar SN, Spies NC, Morgensztern D, Waligorski J, Ponce J, Fulton RS, Maggi LB, Weber JD, Watson MA, O'Conor CJ, Ritter JH, Olsen RR, Cheng H, Mukhopadhyay A, Can I, Cessna MH, Oliver TG, Mardis ER, Wilson RK, Griffith M, Griffith OL, Govindan R

Abstract
Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.

PMID: 30224629 [PubMed - in process]

Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis.

J Hum Genet. 2018 May;63(5):563-568

Authors: Catania A, Ardissone A, Verrigni D, Legati A, Reyes A, Lamantea E, Diodato D, Tonduti D, Imperatore V, Pinto AM, Moroni I, Bertini E, Robinson A, Carrozzo R, Zeviani M, Ghezzi D

Abstract
Biallelic mutations in NDUFAF6 have been identified as responsible for cases of autosomal recessive Leigh syndrome associated with mitochondrial complex I deficiency. Here we report two siblings and two unrelated subjects with Leigh syndrome, in which we found the same compound heterozygous missense (c.532G>C:p.A178P) and deep intronic (c.420+784C>T) variants in NDUFAF6. We demonstrated that the identified intronic variant creates an alternative splice site, leading to the production of an aberrant transcript. A detailed analysis of whole-exome sequencing data together with the functional validation based on mRNA analysis may reveal pathogenic variants even in non-exonic regions.

PMID: 29531337 [PubMed - indexed for MEDLINE]

Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach.

Dialogues Clin Neurosci. 2017 12;19(4):353-371

Authors: Fernandez BA, Scherer SW

Abstract
Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions diagnosed solely on the basis of behavioral assessments that reveal social deficits. Progress has been made in understanding its genetic underpinnings, but most ASD-associated genetic variants, which include copy number variants (CNVs) and mutations in ASD-risk genes, account for no more than 1 % of ASD cases. This high level of genetic heterogeneity leads to challenges obtaining and interpreting genetic testing in clinical settings. The traditional definition of syndromic ASD is a disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. Most have a known genetic cause. Examples include fragile X syndrome and tuberous sclerosis complex. We propose dividing syndromic autism into the following two groups: (i) ASD that occurs in the context of a clinically defined syndrome-recognizing these disorders depends on the familiarity of the clinician with the features of the syndrome, and the diagnosis is typically confirmed by targeted genetic testing (eg, mutation screening of FMR1); (ii) ASD that occurs as a feature of a molecularly defined syndrome-for this group of patients, ASD-associated variants are identified by genome-wide testing that is not hypothesis driven (eg, microarray, whole exome sequencing). These ASD groups cannot be easily clinically defined because patients with a given variant have variable somatic abnormalities (dysmorphism and birth defects). In this article, we review common diagnoses from the above categories and suggest a testing strategy for patients, guided by determining whether the individual has essential or complex ASD; patients in the latter group have multiple morphologic anomalies on physical examination. Finally, we recommend that the syndromic versus nonsyndromic designation ultimately be replaced by classification of ASD according to its genetic etiology, which will inform about the associated spectrum and penetrance of neurobehavioral and somatic manifestations.

PMID: 29398931 [PubMed - indexed for MEDLINE]

Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma.

Nat Commun. 2017 11 28;8(1):1819

Authors: Gonzalez-Meljem JM, Haston S, Carreno G, Apps JR, Pozzi S, Stache C, Kaushal G, Virasami A, Panousopoulos L, Mousavy-Gharavy SN, Guerrero A, Rashid M, Jani N, Goding CR, Jacques TS, Adams DJ, Gil J, Andoniadou CL, Martinez-Barbera JP

Abstract
Senescent cells may promote tumour progression through the activation of a senescence-associated secretory phenotype (SASP), whether these cells are capable of initiating tumourigenesis in vivo is not known. Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2- cells in a paracrine manner. Here, we uncover the mechanisms underlying this paracrine tumourigenesis. We show that expression of oncogenic β-catenin in Hesx1+ embryonic precursors also results in stem cell clusters and paracrine tumours. We reveal that human and mouse clusters are analogous and share a common signature of senescence and SASP. Finally, we show that mice with reduced senescence and SASP responses exhibit decreased tumour-inducing potential. Together, we provide evidence that senescence and a stem cell-associated SASP drive cell transformation and tumour initiation in vivo in an age-dependent fashion.

PMID: 29180744 [PubMed - indexed for MEDLINE]

New ocular finding in Baraitser-Winter syndrome (BWS).

Eur J Med Genet. 2018 Jan;61(1):21-23

Authors: Rall N, Leon A, Gomez R, Daroca J, Lacassie Y

Abstract
Baraitser-Winter syndrome was first described as a syndrome of iris coloboma, ptosis, hypertelorism, and mental retardation (Baraitser and Winter 1988; Baraitser, 2016). The phenotypic spectrum has since broadened to include other facial dysmorphic features, deafness, microcephaly, lissencephaly, and CNS findings (Baraitser and Winter 1988; Ganesh et al., 2005; Henedy et al., 2010; Verloes et al., 2015). The syndrome is due to pathogenic variants on either ACTB or ACTG1 genes (Di Donato et al., 2014; Rivière et al., 2012). There is still discussion which gene variant produces a more severe phenotype (Di Donato et al., 2016; Di Donato et al., 2014; Verloes et al., 2015). We report a 3-year-old girl with short stature, mild global developmental delay, minor brain anomalies and few dysmorphic features including unusual stroma of the irises and unreported corectopia. Exome sequencing reported a de novo likely pathogenic variant on the ACTB gene. The present report adds a new ocular finding to the phenotypic spectrum.

PMID: 29024830 [PubMed - indexed for MEDLINE]

Genetic variation: ExAC boosts clinical variant interpretation in rare diseases.

Nat Rev Genet. 2016 09 15;17(10):584

Authors: Bahcall OG

PMID: 27629930 [PubMed - indexed for MEDLINE]

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IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid.

J Autoimmun. 2018 Sep 12;:

Authors: Chakievska L, Holtsche MM, Künstner A, Goletz S, Petersen BS, Thaci D, Ibrahim SM, Ludwig RJ, Franke A, Sadik CD, Zillikens D, Hölscher C, Busch H, Schmidt E

Abstract
IL-17A has been identified as key regulatory molecule in several autoimmune and chronic inflammatory diseases followed by the successful use of anti-IL-17 therapy, e.g. in ankylosing spondylitis and psoriasis. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease with a high need for more specific, effective and safe treatment options. The aim of this study was to clarify the pathophysiological importance of IL-17A in BP. We found elevated numbers of IL-17A+ CD4+ lymphocytes in the peripheral blood of BP patients and identified CD3+ cells as major source of IL-17A in early BP skin lesions. IL17A and related genes were upregulated in BP skin and exome sequencing of 51 BP patients revealed mutations in twelve IL-17-related genes in 18 patients. We have subsequently found several lines of evidence suggesting a significant role of IL-17A in the BP pathogenesis: (i) IL-17A activated human neutrophils in vitro, (ii) inhibition of dermal-epidermal separation in cryosections of human skin incubated with anti-BP180 IgG and subsequently with anti-IL-17A IgG-treated leukocytes, (iii) close correlation of serum IL-17A levels and diseases activity in a mouse model of BP, (iv) IL17A-deficient mice were protected against autoantibody-induced BP, and (v) pharmacological inhibition of lL-17A reduced the induction of BP in mice. Our data give evidence for a pivotal role of IL-17A in the pathophysiology of BP and advocate IL-17A inhibition as potential novel treatment for this disease.

PMID: 30219389 [PubMed - as supplied by publisher]

Hyperphosphatasia with mental retardation syndrome type 4 In two siblings-expanding the phenotypic and mutational spectrum.

Eur J Med Genet. 2018 Sep 11;:

Authors: Akgün Doğan Ö, Demir GÜ, Koşukçu C, Taskiran EZ, Simsek-Kiper PÖ, Utine GE, Alikaşifoğlu M, Boduroğlu K

Abstract
Hyperphosphatasia with mental retardation syndrome (HPMRS) (OMIM # 239300), is an autosomal recessive disease with phenotypic variability, ranging from mild nonsyndromic intellectual disability to syndromic form with severe intellectual disability, seizures, elevated alkaline phosphatase, brachytelephalangy and facial dysmorphism, Six subgroups of HPMRS were defined in which pathogenic mutations affect genes involved in either synthesis or remodeling of the anchor proteins. Among these, PGAP3 mutations are associated with HPMRS type 4. We report two siblings with a novel homozygous variant in PGAP3 expanding both the phenotypic findings and the mutational spectrum of HPMRS type 4. Developmental delay, hypotonia, facial dysmorphism were the consistent findings with HPMRS in our patients. Large anterior fontanel size, gum hypertrophy, pes equinovarus, concentric ventricle hypertrophy, frontoparietal atrophy and dysphagia were the findings of our patients that have been reported for the first time in this syndrome. Although there is an extensive list of differential diagnoses in patients with developmental delay and hypotonia, the recognizable pattern of facial features, parental consanguinity and mild to moderate serum ALP elevation should be sufficiently suggestive of HPMRS type 4.

PMID: 30217754 [PubMed - as supplied by publisher]

Secondary findings in 421 whole exome-sequenced Chinese children.

Hum Genomics. 2018 Sep 14;12(1):42

Authors: Chen W, Li W, Ma Y, Zhang Y, Han B, Liu X, Zhao K, Zhang M, Mi J, Fu Y, Zhou Z

Abstract
BACKGROUND: Variants with known or possible pathogenicity located in genes that are unrelated to primary disease conditions are defined as secondary findings. Secondary findings are not the primary targets of whole exome and genome sequencing (WES/WGS) assay but can be of great practical value in early disease prevention and intervention. The driving force for this study was to investigate the impact of racial difference and disease background on secondary findings. Here, we analyzed secondary findings frequencies in 421 whole exome-sequenced Chinese children who are phenotypically normal or bear congenital heart diseases/juvenile obesity. In total, 421 WES datasets were processed for potential deleterious variant screening. A reference gene list was defined according to the American College of Medical Genetics and Genomics (ACMG) recommendations for reporting secondary findings v2.0 (ACMG SF v2.0). The variant classification was performed according to the evidence-based guidelines recommended by the joint consensus of the ACMG and the Association for Molecular Pathology (AMP).
RESULTS: Among the 421 WES datasets, we identified 11 known/expected pathogenic variants in 12 individuals, accounting for 2.85% of our samples, which is much higher than the reported frequency in a Caucasian population. In conclusion, secondary findings are not so rare in Chinese children, which means that we should pay more attention to the clinical interpretation of sequencing results.

PMID: 30217213 [PubMed - in process]