Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.

Abstract:

:Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.

journal_name

Am J Hum Genet

authors

Chen DH,Below JE,Shimamura A,Keel SB,Matsushita M,Wolff J,Sul Y,Bonkowski E,Castella M,Taniguchi T,Nickerson D,Papayannopoulou T,Bird TD,Raskind WH

doi

10.1016/j.ajhg.2016.04.009

subject

Has Abstract

pub_date

2016-06-02 00:00:00

pages

1146-1158

issue

6

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(16)30104-5

journal_volume

98

pub_type

杂志文章
  • The 47,XYY male, Y chromosome, and tooth size.

    abstract::Permanent teeth of 12 individuals with a 47,XYY chromosome constitution have been examined. The tooth sizes of 47,XYY males were found to be larger than those of control males and females. In many instances the differences were statistically significant. Using these results, it was possible to conclude that a factor ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Alvesalo L,Osborne RH,Kari M

    更新日期:1975-01-01 00:00:00

  • An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome.

    abstract::The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/375144

    authors: Jaeger EE,Woodford-Richens KL,Lockett M,Rowan AJ,Sawyer EJ,Heinimann K,Rozen P,Murday VA,Whitelaw SC,Ginsberg A,Atkin WS,Lynch HT,Southey MC,Debinski H,Eng C,Bodmer WF,Talbot IC,Hodgson SV,Thomas HJ,Tomlinson IP

    更新日期:2003-05-01 00:00:00

  • Identification of two cosmids derived from within chromosomal band 3p21.1 that contain clusters of rare restriction sites and evolutionarily conserved sequences.

    abstract::We have isolated large numbers of human recombinants from a cosmid library constructed from an interspecific (hamster/human) somatic cell hybrid whose only human component is an intact chromosome 3. Unique sequence probes were isolated from these recombinants and were used to localize them along the length of chromoso...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Smith DI,Golembieski W,Drabkin H,Kiousis S

    更新日期:1989-09-01 00:00:00

  • Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35.

    abstract::Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,meta分析

    doi:10.1086/422475

    authors: Marazita ML,Murray JC,Lidral AC,Arcos-Burgos M,Cooper ME,Goldstein T,Maher BS,Daack-Hirsch S,Schultz R,Mansilla MA,Field LL,Liu YE,Prescott N,Malcolm S,Winter R,Ray A,Moreno L,Valencia C,Neiswanger K,Wyszynski DF,

    更新日期:2004-08-01 00:00:00

  • The tyrosinase-positive oculocutaneous albinism gene shows locus homogeneity on chromosome 15q11-q13 and evidence of multiple mutations in southern African negroids.

    abstract::Tyrosinase-positive oculocutaneous albinism (ty-pos OCA) is an autosomal recessive disorder of the melanin pigmentary system. South African ty-pos OCA individuals occur with two distinct phenotypes, with or without darkly pigmented patches (ephelides, or dendritic freckles) on exposed areas of the skin. These phenotyp...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Kedda MA,Stevens G,Manga P,Viljoen C,Jenkins T,Ramsay M

    更新日期:1994-06-01 00:00:00

  • Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia.

    abstract::Myoclonus-dystonia (M-D) is a movement disorder characterized by rapid muscle contractions and sustained twisting and repetitive movements and has recently been associated with mutations in the epsilon-sarcoglycan gene (SGCE). The mode of inheritance is autosomal dominant with reduced penetrance upon maternal transmis...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/344531

    authors: Müller B,Hedrich K,Kock N,Dragasevic N,Svetel M,Garrels J,Landt O,Nitschke M,Pramstaller PP,Reik W,Schwinger E,Sperner J,Ozelius L,Kostic V,Klein C

    更新日期:2002-12-01 00:00:00

  • Cardiovascular risk factors in a French-Canadian population: resolution of genetic and familial environmental effects on blood pressure by using extensive information on environmental correlates.

    abstract::Genetic and environmental influences on systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MBP) were examined in 371 French-Canadian families by using path analysis. Familial environment was estimated with environmental indices constructed from as many as 14 (of a pool of ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Pérusse L,Rice T,Bouchard C,Vogler GP,Rao DC

    更新日期:1989-08-01 00:00:00

  • Linkage disequilibrium mapping of the gene for Margarita Island ectodermal dysplasia (ED4) to 11q23.

    abstract::Margarita Island ectodermal dysplasia (ED4) is an autosomal recessive disorder characterized by unusual facies, dental anomalies, hypotrichosis, palmoplantar hyperkeratosis and onychodysplasia, syndactyly, and cleft lip/cleft palate. We have used an affected-only DNA-pooling strategy to carry out linkage disequilibriu...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302072

    authors: Suzuki K,Bustos T,Spritz RA

    更新日期:1998-10-01 00:00:00

  • Genome-wide comparison of African-ancestry populations from CARe and other cohorts reveals signals of natural selection.

    abstract::The study of recent natural selection in human populations has important applications to human history and medicine. Positive natural selection drives the increase in beneficial alleles and plays a role in explaining diversity across human populations. By discovering traits subject to positive selection, we can better...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2011.07.025

    authors: Bhatia G,Patterson N,Pasaniuc B,Zaitlen N,Genovese G,Pollack S,Mallick S,Myers S,Tandon A,Spencer C,Palmer CD,Adeyemo AA,Akylbekova EL,Cupples LA,Divers J,Fornage M,Kao WH,Lange L,Li M,Musani S,Mychaleckyj JC,Og

    更新日期:2011-09-09 00:00:00

  • Identification of a new candidate locus for uric acid nephrolithiasis.

    abstract::Renal stone formation is a common multifactorial disorder, of unknown etiology, with an established genetic contribution. Lifetime risk for nephrolithiasis is approximately 10% in Western populations, and uric acid stones account for 5%-10% of all stones, depending on climatic, dietary, and ethnic differences. We stud...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/320105

    authors: Ombra MN,Forabosco P,Casula S,Angius A,Maestrale G,Petretto E,Casu G,Colussi G,Usai E,Melis P,Pirastu M

    更新日期:2001-05-01 00:00:00

  • Genetics of acheiropodia (the handless and footless families of Brazil). VI. Formal genetic analysis.

    abstract::A genetic analysis is presented of data from 22 Brazilian sibships with cases of acheiropodia (the handless and footless families of Brazil). Segregation analysis performed using a 16K CDC 3100 computer showed a segregation frequency of .245 +/- .040, which is close to the expected value of .25. No sporadic cases wer...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Freire-Maia A,Freire-Maia N,Morton NE,Azevêdo ES,Quelce-Salgado A

    更新日期:1975-07-01 00:00:00

  • Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics.

    abstract::The introduction of stochastic methods in pedigree analysis has enabled geneticists to tackle computations intractable by standard deterministic methods. Until now these stochastic techniques have worked by running a Markov chain on the set of genetic descent states of a pedigree. Each descent state specifies the path...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Sobel E,Lange K

    更新日期:1996-06-01 00:00:00

  • A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.

    abstract::Catecholamine-induced polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress. Two modes of inheritance have been described: autosomal dominant and autosomal recessive. Mutations in the ryanodine receptor 2 gene ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/324565

    authors: Lahat H,Pras E,Olender T,Avidan N,Ben-Asher E,Man O,Levy-Nissenbaum E,Khoury A,Lorber A,Goldman B,Lancet D,Eldar M

    更新日期:2001-12-01 00:00:00

  • The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease.

    abstract::The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset < 60 years), and late-onset families. A genetic association was observed between apolipo...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Yu CE,Payami H,Olson JM,Boehnke M,Wijsman EM,Orr HT,Kukull WA,Goddard KA,Nemens E,White JA

    更新日期:1994-04-01 00:00:00

  • Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.

    abstract::Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional a...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2017.09.018

    authors: Sanna-Cherchi S,Khan K,Westland R,Krithivasan P,Fievet L,Rasouly HM,Ionita-Laza I,Capone VP,Fasel DA,Kiryluk K,Kamalakaran S,Bodria M,Otto EA,Sampson MG,Gillies CE,Vega-Warner V,Vukojevic K,Pediaditakis I,Makar GS,M

    更新日期:2017-11-02 00:00:00

  • Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression.

    abstract::The fragile X syndrome is due to the new class of dynamic mutations. It is associated with an expansion of a trinucleotide repeat (CGG) in exon 1 of the fragile X mental retardation gene 1 gene (FMR1). Here we present a fragile X family with an unique female patient who was rendered hemizygous for the FRAXA locus due ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/514872

    authors: Grønskov K,Hjalgrim H,Bjerager MO,Brøndum-Nielsen K

    更新日期:1997-10-01 00:00:00

  • Genetic linkage of hyper-IgE syndrome to chromosome 4.

    abstract::The hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated levels of serum IgE. HIES is now recognized as a multisystem disorder, with nonimmunologic abnormalities of the dentition, bones, and connective tissue. HIES can be transmitted as ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302547

    authors: Grimbacher B,Schäffer AA,Holland SM,Davis J,Gallin JI,Malech HL,Atkinson TP,Belohradsky BH,Buckley RH,Cossu F,Español T,Garty BZ,Matamoros N,Myers LA,Nelson RP,Ochs HD,Renner ED,Wellinghausen N,Puck JM

    更新日期:1999-09-01 00:00:00

  • A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci.

    abstract::Generalized vitiligo is a common autoimmune disorder characterized by the development of white patches of skin and overlying hair due to loss of pigment-forming melanocytes from the involved areas. Family clustering of cases is not uncommon, in a pattern suggestive of multifactorial, polygenic inheritance, and there i...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/375451

    authors: Fain PR,Gowan K,LaBerge GS,Alkhateeb A,Stetler GL,Talbert J,Bennett DC,Spritz RA

    更新日期:2003-06-01 00:00:00

  • Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9.

    abstract::The authors had previously mapped a new locus-DFNA17, for nonsyndromic hereditary hearing impairment-to chromosome 22q12.2-q13. 3. DFNA17 spans a 17- to 23-cM region, and MYH9, a nonmuscle-myosin heavy-chain gene, is located within the linked region. Because of the importance of myosins in hearing, MYH9 was tested as ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/S0002-9297(07)62942-5

    authors: Lalwani AK,Goldstein JA,Kelley MJ,Luxford W,Castelein CM,Mhatre AN

    更新日期:2000-11-01 00:00:00

  • Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36.

    abstract::Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. Studies of BMD in families and twins have shown that this trait is under strong genetic control. To identify regions of the genome that contain quantitative trait loci (QTL) for BMD, we performed independent genomewide screens, using two ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/345819

    authors: Wilson SG,Reed PW,Bansal A,Chiano M,Lindersson M,Langdown M,Prince RL,Thompson D,Thompson E,Bailey M,Kleyn PW,Sambrook P,Shi MM,Spector TD

    更新日期:2003-01-01 00:00:00

  • Chromosomal haplotypes by genetic phasing of human families.

    abstract::Assignment of alleles to haplotypes for nearly all the variants on all chromosomes can be performed by genetic analysis of a nuclear family with three or more children. Whole-genome sequence data enable deterministic phasing of nearly all sequenced alleles by permitting assignment of recombinations to precise chromoso...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2011.07.023

    authors: Roach JC,Glusman G,Hubley R,Montsaroff SZ,Holloway AK,Mauldin DE,Srivastava D,Garg V,Pollard KS,Galas DJ,Hood L,Smit AF

    更新日期:2011-09-09 00:00:00

  • Narrowing the position of the Treacher Collins syndrome locus to a small interval between three new microsatellite markers at 5q32-33.1.

    abstract::Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCOF1 locus has been localized to chromosome 5q32-33.2. In the present study we have used the combined techniques of genetic linkage analysis and ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Dixon MJ,Dixon J,Houseal T,Bhatt M,Ward DC,Klinger K,Landes GM

    更新日期:1993-05-01 00:00:00

  • Spin label electron paramagnetic resonance (EPR) studies of Huntington disease erythrocyte membranes.

    abstract::Several spin-label electron paramagnetic resonance (EPR) studies of red cell membranes appear to show abnormalities in some Huntington disease (HD) patients, but not in others. Both studies measure the W/S ratios, presumably under similar conditions, but have different results. We have studied the W/S ratio in some de...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Fung LW,Ostrowski MS

    更新日期:1982-05-01 00:00:00

  • Age trends in human chiasma frequencies and recombination fractions. I. Chiasma frequencies.

    abstract::Chiasma frequency data on 183 males were subjected to an analysis of covariance. There appeared to be little or no linear trend in chiasma frequency with age. This conclusion was supported by a detailed analysis of chiasma frequencies for each autosome from 21 males. There were, however, significant differences among ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Lange K,Page BM,Elston RC

    更新日期:1975-05-01 00:00:00

  • Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma.

    abstract::Timely molecular diagnosis of RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecu...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/345651

    authors: Richter S,Vandezande K,Chen N,Zhang K,Sutherland J,Anderson J,Han L,Panton R,Branco P,Gallie B

    更新日期:2003-02-01 00:00:00

  • Strong Amerind/white sex bias and a possible Sephardic contribution among the founders of a population in northwest Colombia.

    abstract::Historical and genetic evidences suggest that the recently founded population of Antioquia (Colombia) is potentially useful for the genetic mapping of complex traits. This population was established in the 16th-17th centuries through the admixture of Amerinds, Europeans, and Africans and grew in relative isolation unt...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/S0002-9297(07)62956-5

    authors: Carvajal-Carmona LG,Soto ID,Pineda N,Ortíz-Barrientos D,Duque C,Ospina-Duque J,McCarthy M,Montoya P,Alvarez VM,Bedoya G,Ruiz-Linares A

    更新日期:2000-11-01 00:00:00

  • Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism.

    abstract::Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a gene...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/342732

    authors: Smalley SL,Kustanovich V,Minassian SL,Stone JL,Ogdie MN,McGough JJ,McCracken JT,MacPhie IL,Francks C,Fisher SE,Cantor RM,Monaco AP,Nelson SF

    更新日期:2002-10-01 00:00:00

  • The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population.

    abstract::Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is an autosomal recessive progressive encephalopathy of childhood enriched in the western part of Finland, with a local incidence of 1 in 1500. We recently assigned the locus for vLINCL, CLN5, to 13q21.1-q32. In the present study, the haplotype analysis of...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Varilo T,Savukoski M,Norio R,Santavuori P,Peltonen L,Järvelä I

    更新日期:1996-03-01 00:00:00

  • Leveraging Polygenic Functional Enrichment to Improve GWAS Power.

    abstract::Functional genomics data has the potential to increase GWAS power by identifying SNPs that have a higher prior probability of association. Here, we introduce a method that leverages polygenic functional enrichment to incorporate coding, conserved, regulatory, and LD-related genomic annotations into association analyse...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2018.11.008

    authors: Kichaev G,Bhatia G,Loh PR,Gazal S,Burch K,Freund MK,Schoech A,Pasaniuc B,Price AL

    更新日期:2019-01-03 00:00:00

  • Pitfalls in the molecular genetic diagnosis of Leber hereditary optic neuropathy (LHON).

    abstract::Pathogenetic mutations in mtDNA are found in the majority of patients with Leber hereditary optic neuropathy (LHON), and molecular genetic techniques to detect them are important for the diagnosis. A false-positive molecular genetic error has adverse consequences for the diagnosis of this maternally inherited disease....

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Johns DR,Neufeld MJ

    更新日期:1993-10-01 00:00:00