A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.

Eur J Neurol. 2018 Mar 12;:

Authors: Rydning SL, Dudesek A, Rimmele F, Funke C, Krüger S, Biskup S, Vigeland MD, Hjorthaug HS, Sejersted Y, Tallaksen C, Selmer KK, Kamm C

Abstract
BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSP) are clinically and genetically heterogenous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families.
METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function predicted by bioinformatic prediction tools.
RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease.
CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, we describe the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP. This article is protected by copyright. All rights reserved.

PMID: 29528531 [PubMed - as supplied by publisher]

Hereditary kidney cancer syndromes: Genetic disorders driven by alterations in metabolism and epigenome regulation.

Cancer Sci. 2018 Mar;109(3):581-586

Authors: Hasumi H, Yao M

Abstract
Although hereditary kidney cancer syndrome accounts for approximately five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, USA and the first kidney cancer-associated gene, VHL, was identified through kindred analysis of von Hippel-Lindau (VHL) syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided the basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at the germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of the causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms of how an alteration of each kidney cancer-associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer.

PMID: 29325224 [PubMed - indexed for MEDLINE]

Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate.

Birth Defects Res. 2017 01 20;109(1):27-37

Authors: Liu H, Busch T, Eliason S, Anand D, Bullard S, Gowans LJJ, Nidey N, Petrin A, Augustine-Akpan EA, Saadi I, Dunnwald M, Lachke SA, Zhu Y, Adeyemo A, Amendt B, Roscioli T, Cornell R, Murray J, Butali A

Abstract
BACKGROUND: Recent advances in genomics methodologies, in particular the availability of next-generation sequencing approaches have made it possible to identify risk loci throughout the genome, in particular the exome. In the current study, we present findings from an exome study conducted in five affected individuals of a multiplex family with cleft palate only.
METHODS: The GEnome MINIng (GEMINI) pipeline was used to functionally annotate the single nucleotide polymorphisms, insertions and deletions. Filtering methods were applied to identify variants that are clinically relevant and present in affected individuals at minor allele frequencies (≤1%) in the 1000 Genomes Project single nucleotide polymorphism database, Exome Aggregation Consortium, and Exome Variant Server databases. The bioinformatics tool Systems Tool for Craniofacial Expression-Based Gene Discovery was used to prioritize cleft candidates in our list of variants, and Sanger sequencing was used to validate the presence of identified variants in affected and unaffected relatives.
RESULTS: Our analyses approach narrowed the candidates down to the novel missense variant in ARHGAP29 (GenBank: NM_004815.3, NP_004806.3;c.1654T>C [p.Ser552Pro]. A functional assay in zebrafish embryos showed that the encoded protein lacks the activity possessed by its wild-type counterpart, and migration assays revealed that keratinocytes transfected with wild-type ARHGAP29 migrated faster than counterparts transfected with the p.Ser552Pro ARHGAP29 variant or empty vector (control).
CONCLUSION: These findings reveal ARHGAP29 to be a regulatory protein essential for proper development of the face, identifies an amino acid that is key for this, and provides a potential new diagnostic tool.Birth Defects Research 109:27-37, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 28029220 [PubMed - indexed for MEDLINE]

Whole-exome sequencing identifies rare compound heterozygous mutations in the MYBPC3 gene associated with severe familial hypertrophic cardiomyopathy.

Eur J Med Genet. 2018 Mar 07;:

Authors: Zhou N, Qin S, Liu Y, Tang L, Zhao W, Pan C, Qiu Z, Wang X, Shu X

Abstract
Most patients with hypertrophic cardiomyopathy have single-gene autosomal dominant mutations in loci that encode for sarcomeric proteins. The aim of this study was to determine whether pathogenic mutations were present by whole-exome sequencing (WES) in two families with hypertrophic cardiomyopathy (HCM) that presented during adolescence. Blood samples and clinical data were collected from individuals in two families with HCM. DNA was extracted. Mutations were identified using whole-exome sequencing (WES), and the genotypes of family members were identified using Sanger sequencing. Compound heterozygous mutations in the MYBPC3 gene (c.659A > G, p.Tyr220Cys; c.772G > A, p.Glu258Lys,NM_000256, Family 1), (c.873delG, p. Ile292PhefsTer8; c.3G > A, p.Met1?, NM_000256, Family 2) were identified by WES. Patient 1 carried the maternally inherited c.659A > G mutation and the paternally inherited c.772G > A mutation. Patient 2 carried the maternally inherited frameshift mutation c.873delG and the paternally inherited mutation c.3G > A. Two families with HCM presenting during adolescence (age of onset is about 11 years old) demonstrated compound heterozygous mutations in the MYBPC3 gene. These findings suggested an association of MYBPC3 mutations with the early onset of symptoms and worsened prognoses. Our study highlights the importance of genetic screening of all family members in cases of HCM.

PMID: 29524613 [PubMed - as supplied by publisher]

Mutations in the fourth β-propeller domain of LRP4 are associated with isolated syndactyly with fusion of the third and fourth fingers.

Hum Mutat. 2018 Mar 10;:

Authors: Sukenik Halevy R, Chien HC, Heinz B, Bamshad MJ, Nickerson DA, Kircher M, Ahituv N

Abstract
Isolated hand syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover two novel variants, chr11 g.46896373C>G; p.D1403H and chr11 g.46893078G>T; p.Q1564K, in LRP4 in a child with isolated bilateral syndactyly of the third and fourth fingers. Each variant was inherited from a different parent and neither parent was affected. Variants in LRP4 have been previously associated with syndactyly in Cenani-Lenz syndactyly syndrome and Sclerosteosis 2, but have not been reported in individuals with isolated syndactyly. LRP4 inhibits LRP6/LRP5-mediated activation of canonical Wnt signaling and mediates sclerostin-dependent inhibition of bone formation. p.D1403H and p.Q1564K are located within the fourth β-propeller of the extracellular protein domain that has yet to be associated with human disease. Functional analyses of p.D1403H and p.Q1564K show that they significantly decrease LRP4's inhibition of Wnt signaling. These results suggest that variants in the fourth β-propeller of the extracellular protein domain may cause a phenotype distinct from previously characterized LRP4 variants. This article is protected by copyright. All rights reserved.

PMID: 29524275 [PubMed - as supplied by publisher]

Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion syndrome: a case report.

BMC Med Genet. 2018 Mar 09;19(1):41

Authors: Cadieux-Dion M, Safina NP, Engleman K, Saunders C, Repnikova E, Raje N, Canty K, Farrow E, Miller N, Zellmer L, Thiffault I

Abstract
BACKGROUND: Ectodermal dysplasias (ED) are a group of diseases that affects the development or function of the teeth, hair, nails and exocrine and sebaceous glands. One type of ED, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC or Hay-Wells syndrome), is an autosomal dominant disease characterized by the presence of skin erosions affecting the palms, soles and scalp. Other clinical manifestations include ankyloblepharon filiforme adnatum, cleft lip, cleft palate, craniofacial abnormalities and ectodermal defects such as sparse wiry hair, nail changes, dental changes, and subjective hypohydrosis.
CASE PRESENTATION: We describe a patient presenting clinical features reminiscent of AEC syndrome in addition to recurrent infections suggestive of immune deficiency. Genetic testing for TP63, IRF6 and RIPK4 was negative. Microarray analysis revealed a 2 MB deletion on chromosome 1 (1q21.1q21.2). Clinical exome sequencing uncovered compound heterozygous variants in CHUK; a maternally-inherited frameshift variant (c.1365del, p.Arg457Aspfs*6) and a de novo missense variant (c.1388C > A, p.Thr463Lys) on the paternal allele.
CONCLUSIONS: To our knowledge, this is the fourth family reported with CHUK-deficiency and the second patient with immune abnormalities. This is the first case of CHUK-deficiency with compound heterozygous pathogenic variants, including one variant that arose de novo. In comparison to cases found in the literature, this patient demonstrates a less severe phenotype than previously described.

PMID: 29523099 [PubMed - in process]

Exome-wide somatic mutation characterization of small bowel adenocarcinoma.

PLoS Genet. 2018 Mar 09;14(3):e1007200

Authors: Hänninen UA, Katainen R, Tanskanen T, Plaketti RM, Laine R, Hamberg J, Ristimäki A, Pukkala E, Taipale M, Mecklin JP, Forsström LM, Pitkänen E, Palin K, Välimäki N, Mäkinen N, Aaltonen LA

Abstract
Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (AI) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.

PMID: 29522538 [PubMed - as supplied by publisher]

Morphogenetic defects underlie Superior Coloboma, a newly identified closure disorder of the dorsal eye.

PLoS Genet. 2018 Mar 09;14(3):e1007246

Authors: Hocking JC, Famulski JK, Yoon KH, Widen SA, Bernstein CS, Koch S, Weiss O, FORGE Canada Consortium, Agarwala S, Inbal A, Lehmann OJ, Waskiewicz AJ

Abstract
The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to reanalyze morphogenesis of the dorsal eye. Our studies revealed the presence of the superior ocular sulcus (SOS), a transient division of the dorsal eye conserved across fish, chick, and mouse. Exome sequencing of superior coloboma patients identified rare variants in a Bone Morphogenetic Protein (Bmp) receptor (BMPR1A) and T-box transcription factor (TBX2). Consistent with this, we find sulcus closure defects in zebrafish lacking Bmp signaling or Tbx2b. In addition, loss of dorsal ocular Bmp is rescued by concomitant suppression of the ventral-specific Hedgehog pathway, arguing that sulcus closure is dependent on dorsal-ventral eye patterning cues. The superior ocular sulcus acts as a conduit for blood vessels, with altered sulcus closure resulting in inappropriate connections between the hyaloid and superficial vascular systems. Together, our findings explain the existence of superior coloboma, a congenital ocular anomaly resulting from aberrant morphogenesis of a developmental structure.

PMID: 29522511 [PubMed - as supplied by publisher]

RSRC1 mutation affects intellect and behaviour through aberrant splicing and transcription, downregulating IGFBP3.

Brain. 2018 Mar 07;:

Authors: Perez Y, Menascu S, Cohen I, Kadir R, Basha O, Shorer Z, Romi H, Meiri G, Rabinski T, Ofir R, Yeger-Lotem E, Birk OS

Abstract
RSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show that RSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show that RSRC1 is ubiquitously expressed, and that the RSRC1 mutation triggers nonsense-mediated mRNA decay of the RSRC1 transcript in patients' fibroblasts. Short hairpin RNA (shRNA)-mediated lentiviral silencing and overexpression of RSRC1 in SH-SY5Y cells demonstrated that RSRC1 has a role in alternative splicing and transcription regulation. Transcriptome profiling of RSRC1-silenced cells unravelled specific differentially expressed genes previously associated with intellectual disability, hypotonia and schizophrenia, relevant to the disease phenotype. Protein-protein interaction network modelling suggested possible intermediate interactions by which RSRC1 affects gene-specific differential expression. Patient-derived induced pluripotent stem cells, differentiated into neural progenitor cells, showed expression dynamics similar to the RSRC1-silenced SH-SY5Y model. Notably, patient neural progenitor cells had 9.6-fold downregulated expression of IGFBP3, whose brain expression is affected by MECP2, aberrant in Rett syndrome. Interestingly, Igfbp3-null mice have behavioural impairment, abnormal synaptic function and monoaminergic neurotransmission, likely correlating with the disease phenotype.

PMID: 29522154 [PubMed - as supplied by publisher]

Coincident myelomeningocele and gastroschisis: report of 2 cases.

J Neurosurg Pediatr. 2018 Mar 09;:1-4

Authors: Hauptman JS, Bollo R, Damerla R, Gibbs B, Lo C, Katz A, Greene S

Abstract
Myelomeningocele and gastroschisis, on their own, are both relatively common entities encountered in pediatric surgical care. Coexistence of these pathologies, however, is exceedingly rare. The authors report on 2 patients who presented with myelomeningocele and gastroschisis at birth. They obtained blood for whole-exome analysis for one of the patients and identified 3 mutations that could be related to the underlying anomalies: homozygous mutations in FAM171B and ABCA1 and a hemizygous (X-linked) mutation in COL4A5. Of these, FAM171B and ABCA1 both have function that may be related to the underlying disease.

PMID: 29521606 [PubMed - as supplied by publisher]

Clinical characterization and diagnosis of cystic fibrosis through exome sequencing in Chinese infants with Bartter-syndrome-like hypokalemia alkalosis.

Front Med. 2018 Mar 09;:

Authors: Qiu L, Yang F, He Y, Yuan H, Zhou J

Abstract
Cystic fibrosis (CF) is a fatal autosomal-recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by recurrent pulmonary infection with obstructive pulmonary disease. CF is common in the Caucasian population but is rare in the Chinese population. The symptoms of early-stage CF are often untypical and may sometimes manifest as Bartter syndrome (BS)-like hypokalemic alkalosis. Therefore, the ability of doctors to differentiate CF from BS-like hypokalemic alkalosis in Chinese infants is a great challenge in the timely and accurate diagnosis of CF. In China, sporadic CF has not been diagnosed in children younger than three years of age to date. Three infants, who were initially admitted to our hospital over the period of June 2013 to September 2014 with BS-like hypokalemic alkalosis, were diagnosed with CF through exome sequencing and sweat chloride measurement. The compound heterozygous mutations of the CFTR gene were detected in two infants, and a homozygous missense mutation was found in one infant. Among the six identified mutations, two are novel point mutations (c.1526G > C and c.3062C > T) that are possibly pathogenic. The three infants are the youngest Chinese patients to have been diagnosed with sporadic CF at a very early stage. Follow-up examination showed that all of the cases remained symptom-free after early intervention, indicating the potential benefit of very early diagnosis and timely intervention in children with CF. Our results demonstrate the necessity of distinguishing CF from BS in Chinese infants with hypokalemic alkalosis and the significant diagnostic value of powerful exome sequencing for rare genetic diseases. Furthermore, our findings expand the CFTR mutation spectrum associated with CF.

PMID: 29520692 [PubMed - as supplied by publisher]

De novo HDAC8 mutation causes Rett-related disorder with distinctive facial features and multiple congenital anomalies.

Brain Dev. 2018 Mar 05;:

Authors: Saikusa T, Hara M, Iwama K, Yuge K, Ohba C, Okada JI, Hisano T, Yamashita Y, Okamoto N, Saitsu H, Matsumoto N, Matsuishi T

Abstract
We present a unique 11-year-old girl showing clinical features of Rett-related disorder with distinctive facial features and multiple congenital anomalies including ocular hypertelorism, arched eyebrows, a broad nose, dental anomalies, congenital heart disease, truncal obesity, and epilepsy. A novel de novo mutation in histone deacetylase 8 (HDAC8) (c.652G > T, p.Gly218Cys) was confirmed by whole exome sequencing and Sanger sequencing. X-chromosome inactivation analysis on DNA isolated from peripheral blood lymphocytes revealed a completely skewed pattern associated with an inactive maternal allele. Late clinical loss of acquired purposeful hand movements and psychomotor deterioration may be a feature of Rett-related disorder, while distinctive facial features and multiple congenital anomalies are reminiscent of Cornelia de Lange syndrome.

PMID: 29519750 [PubMed - as supplied by publisher]

[DARS mutations responsible for hypomyelination with brain stem and spinal cord involvement and leg spasticity: report of two cases and review of literature].

Zhonghua Er Ke Za Zhi. 2018 Mar 02;56(3):211-215

Authors: Zhang J, Liu M, Zhou L, Zhang ZB, Wang JM, Jiang YW, Wu Y

Abstract
Objective: To analyze the clinical and imaging features of hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) due to mutations in DARS, and to identify DARS mutations responsible for HBSL. Methods: Data on 2 HBSL patients who were admitted to the pediatric department of Peking University First Hospital from January 2009 through December 2016 were reviewed and the 2 patients were followed up. Targeted next generation sequencing, whole exome sequencing and Sanger sequencing were employed to identify potential genetic variations of the children and their parents. The clinical manifestations, MRI features and genotypic characteristics of two patients were reviewed, and the literature was reviewed. HBSL reported cases were searched with"leukoencephalopathies, DARS"on databases of PubMed, Wanfang, China National Knowledge Infrastructure and VIP from 1975 to 2017. The clinical manifestations and molecular features were analyzed. Results: Both patients showed delayed motor development, but had normal cognitive development. At the age of 8 years, case 1 reached the most significant motor development milestone of only standing with help during the last follow-up. At the age of 9, case 2 could walk independently during the last follow-up. On physical examination, both showed leg spastcity, active tendon reflex, positive Babinski sign. Both patients had brain MRI findings of high T2WI signal in bilateral deep cerebral white matter, slightly lower T1WI, and no abnormal DWI signal. Lesions of case 1 were relatively extensive and involved subcortical white matter, corpus callosum and internal capsule. Spinal MRI scans for both patients showed no abnormal signals. Novel mutations in DARS gene-namely, c.1498_1499insTCA (p.500_501insIle) and c.1210A>G (p.Met404Val) , c.1432A>G (p.Met478Val) and c.1210A>G (p.Met404Val) were identified in case 1 and case 2 respectively. On the database, 2 reports involving 13 foreign patients were retrieved. The age of disease onset was from 4 months to 18 years, and their initial symptoms were development delay or regression. Most of them presented with progressive lower extremity spasm, and the brain magnetic resonance imaging was characterized by hypomyelination in white matter. Clinical phenotypes of different age groups were significantly different. Conclusion: We have reported two patients with HBSL in China, and 3 novel mutations in DARS, which is helpful for the diagnosis and genetic counseling of HBSL.

PMID: 29518832 [PubMed - in process]

Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia.

Oncotarget. 2017 May 23;8(21):34687-34697

Authors: Li Q, Li B, Hu L, Ning H, Jiang M, Wang D, Liu T, Zhang B, Chen H

Abstract
The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice. Moreover, a high sensitivity to the JAK1/2 inhibitor ruxolitinib was observed in S646P mutant model. Exploration in a total of 209 ALL cases showed that JAK1 mutations occur at a frequency of 10.5% in T-ALL (2/19) and 1.6% in B-ALL (3/190). Collectively, our results suggested that JAK1 S646P is an activating mutation in vitro and in vivo. JAK-STAT pathway might represent a promising therapeutic target for ALL.

PMID: 28410228 [PubMed - indexed for MEDLINE]

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease.

Hum Mol Genet. 2018 Mar 06;:

Authors: Peter B, Waddington CL, Oláhová M, Sommerville EW, Hopton S, Pyle A, Champion M, Ohlson M, Siibak T, Chrzanowska-Lightowlers ZMA, Taylor RW, Falkenberg M, Lightowlers RN

Abstract
LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively-inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T>C predicting p.(Tyr565His) and c.2197G>A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense (p.(Glu733Lys)) variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically-relevant tissues.

PMID: 29518248 [PubMed - as supplied by publisher]

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

Genet Med. 2018 Mar 08;:

Authors: Boczonadi V, King MS, Smith AC, Olahova M, Bansagi B, Roos A, Eyassu F, Borchers C, Ramesh V, Lochmüller H, Polvikoski T, Whittaker RG, Pyle A, Griffin H, Taylor RW, Chinnery PF, Robinson AJ, Kunji ERS, Horvath R

Abstract
PurposeTo understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.MethodsWe identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.ResultsThe patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.ConclusionMitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.GENETICS in MEDICINE advance online publication, 8 March 2018; doi:10.1038/gim.2017.251.

PMID: 29517768 [PubMed - as supplied by publisher]

Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature.

Front Oncol. 2018;8:32

Authors: Ayres-Silva JP, Bonamino MH, Gouveia ME, Monte-Mor BCR, Coutinho DF, Daumas AH, Solza C, Braggio E, Zalcberg IR

Abstract
The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

PMID: 29515972 [PubMed]

Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant.

JCI Insight. 2018 Mar 08;3(5):

Authors: Jacoby MA, Duncavage EJ, Chang GS, Miller CA, Shao J, Elliott K, Robinson J, Fulton RS, Fronick CC, O'Laughlin M, Heath SE, Pusic I, Welch JS, Link DC, DiPersio JF, Westervelt P, Ley TJ, Graubert TA, Walter MJ

Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. Newly acquired structural variants (SVs) were present in an emergent/expanding subclone in 8 of 9 patients at progression, implicating the acquisition of SVs as important late subclonal progression events. In addition, pretransplant therapy with azacitidine likely influenced the mutation spectrum and evolution of emergent subclones after alloHCT. Although subclone evolution is common, founding clone mutations are always present at progression and could be detected in the bone marrow as early as 30 and/or 100 days after alloHCT in 6 of 8 (75%) patients, often prior to clinical progression. In conclusion, MDS progression after alloHCT is characterized by subclonal expansion and evolution, which can be influenced by pretransplant therapy.

PMID: 29515031 [PubMed - as supplied by publisher]

Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly.

J Med Genet. 2018 Mar 07;:

Authors: Shabbir RMK, Nalbant G, Ahmad N, Malik S, Tolun A

Abstract
BACKGROUND: Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11-deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred.
METHODS: We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect.
RESULTS: The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects.

PMID: 29514872 [PubMed - as supplied by publisher]

Next generation sequencing-based emerging trends in molecular biology of gastric cancer.

Am J Cancer Res. 2018;8(2):207-225

Authors: Verma R, Sharma PC

Abstract
Gastric cancer (GC) is one of the leading causes of cancer related mortality in the world. Being asymptomatic in nature till advanced stage, diagnosis of gastric cancer becomes difficult in early stages of the disease. The onset and progression of gastric cancer has been attributed to multiple factors including genetic alterations, epigenetic modifications, Helicobacter pylori and Epstein-Barr Virus (EBV) infection, and dietary habits. Next Generation Sequencing (NGS) based approaches viz. Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), RNA-Seq, and targeted sequencing have expanded the knowledge base of molecular pathogenesis of gastric cancer. In this review, we highlight recent NGS-based advances covering various genetic alterations (Microsatellite Instability, Single Nucleotide Variations, and Copy Number Variations), epigenetic changes (DNA methylation, histone modification, microRNAs) and differential gene expression during gastric tumorigenesis. We also briefly discuss the current and future potential biomarkers, drugs and therapeutic approaches available for the management of gastric cancer.

PMID: 29511593 [PubMed]