Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy.

Abstract:

:Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function.

journal_name

Am J Hum Genet

authors

Fry AE,Marra C,Derrick AV,Pickrell WO,Higgins AT,Te Water Naude J,McClatchey MA,Davies SJ,Metcalfe KA,Tan HJ,Mohanraj R,Avula S,Williams D,Brady LI,Mesterman R,Tarnopolsky MA,Zhang Y,Yang Y,Wang X,Genomics England R

doi

10.1016/j.ajhg.2020.10.017

subject

Has Abstract

pub_date

2021-01-07 00:00:00

pages

176-185

issue

1

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(20)30397-9

journal_volume

108

pub_type

杂志文章
  • Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.

    abstract::Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2019.09.017

    authors: Mitani T,Punetha J,Akalin I,Pehlivan D,Dawidziuk M,Coban Akdemir Z,Yilmaz S,Aslan E,Hunter JV,Hijazi H,Grochowski CM,Jhangiani SN,Karaca E,Fatih JM,Iwanowski P,Gambin T,Wlasienko P,Goszczanska-Ciuchta A,Bekiesinska-Fi

    更新日期:2019-11-07 00:00:00

  • A positive modifier of spinal muscular atrophy in the SMN2 gene.

    abstract::Spinal muscular atrophy (SMA) is a common autosomal-recessive motor neuron disease caused by the homozygous loss of the SMN1 gene. A nearly identical gene, SMN2, has been shown to decrease the severity of SMA in a dose-dependent manner. However SMN2 is not the sole phenotypic modifier, because there are discrepant SMA...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2009.08.002

    authors: Prior TW,Krainer AR,Hua Y,Swoboda KJ,Snyder PC,Bridgeman SJ,Burghes AH,Kissel JT

    更新日期:2009-09-01 00:00:00

  • Homozygotes for the autosomal dominant neoplasia syndrome (MEN1).

    abstract::Families in which both parents are heterozygotes for the same autosomal dominant neoplasia syndrome are extremely unusual. Recently, we had the unique opportunity to evaluate three symptomatic siblings from the union between two unrelated individuals affected by multiple endocrine neoplasia type 1 (MEN1). When the thr...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Brandi ML,Weber G,Svensson A,Falchetti A,Tonelli F,Castello R,Furlani L,Scappaticci S,Fraccaro M,Larsson C

    更新日期:1993-12-01 00:00:00

  • Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting.

    abstract::Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2011.05.023

    authors: Saadi I,Alkuraya FS,Gisselbrecht SS,Goessling W,Cavallesco R,Turbe-Doan A,Petrin AL,Harris J,Siddiqui U,Grix AW Jr,Hove HD,Leboulch P,Glover TW,Morton CC,Richieri-Costa A,Murray JC,Erickson RP,Maas RL

    更新日期:2011-07-15 00:00:00

  • Fine mapping of the autosomal dominant split hand/split foot locus on chromosome 7, band q21.3-q22.1.

    abstract::Split hand/split foot (SHFD) is a human developmental defect characterized by missing digits, fusion of remaining digits, and a deep median cleft in the hands and feet. Cytogenetic studies of deletions and translocations associated with this disorder have indicated that an autosomal dominant split hand/split foot locu...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,评审

    doi:

    authors: Scherer SW,Poorkaj P,Allen T,Kim J,Geshuri D,Nunes M,Soder S,Stephens K,Pagon RA,Patton MA

    更新日期:1994-07-01 00:00:00

  • Carrier detection and prenatal diagnosis in Duchenne and Becker muscular dystrophy families, using dinucleotide repeat polymorphisms.

    abstract::To improve carrier detection and prenatal diagnosis for Duchenne and Becker muscular dystrophy families, we determined allele frequencies and measures of variation for four (dC-dA)n.(dG-dT)n loci identified within a deletion-prone region of the human dystrophin gene. The loci are highly polymorphic, with predicted het...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Clemens PR,Fenwick RG,Chamberlain JS,Gibbs RA,de Andrade M,Chakraborty R,Caskey CT

    更新日期:1991-11-01 00:00:00

  • Combined use of biallelic and microsatellite Y-chromosome polymorphisms to infer affinities among African populations.

    abstract::To define Y-chromosome haplotypes, we studied seven biallelic polymorphic sites. We combined data with those from four dinucleotide-repeat polymorphisms, to establish Y-chromosome compound superhaplotypes. Eight biallelic haplotypes that matched the dendrogram proposed by other investigators were identified in 762 Y c...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302538

    authors: Scozzari R,Cruciani F,Santolamazza P,Malaspina P,Torroni A,Sellitto D,Arredi B,Destro-Bisol G,De Stefano G,Rickards O,Martinez-Labarga C,Modiano D,Biondi G,Moral P,Olckers A,Wallace DC,Novelletto A

    更新日期:1999-09-01 00:00:00

  • Genomewide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21-q22. Pima Diabetes Gene Group.

    abstract::On the basis of accumulating evidence that obesity has a substantial genetic component, a genomewide search for linkages of DNA markers to percent body fat is ongoing in Pima Indians, a population with a very high prevalence of obesity. An initial screen of the genome (>600 markers in 874 individuals) has been complet...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Norman RA,Thompson DB,Foroud T,Garvey WT,Bennett PH,Bogardus C,Ravussin E

    更新日期:1997-01-01 00:00:00

  • WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta.

    abstract::Osteogenesis imperfecta (OI) is a heritable disorder that ranges in severity from death in the perinatal period to an increased lifetime risk of fracture. Mutations in COL1A1 and COL1A2, which encode the chains of type I procollagen, result in dominant forms of OI, and mutations in several other genes result in recess...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2013.02.009

    authors: Pyott SM,Tran TT,Leistritz DF,Pepin MG,Mendelsohn NJ,Temme RT,Fernandez BA,Elsayed SM,Elsobky E,Verma I,Nair S,Turner EH,Smith JD,Jarvik GP,Byers PH

    更新日期:2013-04-04 00:00:00

  • Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism.

    abstract::The debrisoquine/sparteine polymorphism is associated with a clinically important genetic deficiency of oxidative drug metabolism. From 5% to 10% of Caucasians designated as poor metabolizers (PMs) of the debrisoquine/sparteine polymorphism have a severely impaired capacity to metabolize more than 25 therapeutically u...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Gaedigk A,Blum M,Gaedigk R,Eichelbaum M,Meyer UA

    更新日期:1991-05-01 00:00:00

  • Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy.

    abstract::The etiology of acquired partial lipodystrophy (APL, also called "Barraquer-Simons syndrome") is unknown. Genomic DNA mutations affecting the nuclear lamina protein lamin A cause inherited partial lipodystrophy but are not found in patients with APL. Because it also encodes a nuclear lamina protein (lamin B2) and its ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/505885

    authors: Hegele RA,Cao H,Liu DM,Costain GA,Charlton-Menys V,Rodger NW,Durrington PN

    更新日期:2006-08-01 00:00:00

  • Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population.

    abstract::Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have no...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2012.02.011

    authors: Srour M,Schwartzentruber J,Hamdan FF,Ospina LH,Patry L,Labuda D,Massicotte C,Dobrzeniecka S,Capo-Chichi JM,Papillon-Cavanagh S,Samuels ME,Boycott KM,Shevell MI,Laframboise R,Désilets V,FORGE Canada Consortium.,Maranda B,

    更新日期:2012-04-06 00:00:00

  • Cytogenetic and molecular analysis of sex-chromosome monosomy.

    abstract::X chromosome- and Y chromosome-specific DNA probes were used to study different aspects of the genesis of sex-chromosome monosomy. Using X-linked RFLPs, we studied the parental origin of the single X chromosome in 35 spontaneously aborted and five live-born 45,X conceptions. We determined the origin in 35 cases; 28 ha...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Hassold T,Benham F,Leppert M

    更新日期:1988-04-01 00:00:00

  • Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.

    abstract::Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that develop from the growth centers of the long bones. EXT is genetically heterogeneous, with three loci, currently identified on chromosomes 8q24.1, 11p13, and 19q. The EXT1 gene, loca...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Hecht JT,Hogue D,Wang Y,Blanton SH,Wagner M,Strong LC,Raskind W,Hansen MF,Wells D

    更新日期:1997-01-01 00:00:00

  • Linkage analysis of chromosome 17 markers in British and South African families with neurofibromatosis type I.

    abstract::Nine markers from the pericentromeric region of chromosome 17 were typed in 16 British and five South African families with neurofibromatosis type 1 (NF1). The markers--p17H8, pHHH202, and EW204--were linked to NF1 at recombination fractions less than 1%. No evidence of locus heterogeneity was detected. Inspection of ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Mathew CG,Thorpe K,Easton DF,Chin KS,Jadayel D,Ponder M,Moore G,Wallis CE,Slater CP,De Jong G

    更新日期:1989-01-01 00:00:00

  • Association between single-nucleotide polymorphisms in selectin genes and immunoglobulin A nephropathy.

    abstract::Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A nephropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/339077

    authors: Takei T,Iida A,Nitta K,Tanaka T,Ohnishi Y,Yamada R,Maeda S,Tsunoda T,Takeoka S,Ito K,Honda K,Uchida K,Tsuchiya K,Suzuki Y,Fujioka T,Ujiie T,Nagane Y,Miyano S,Narita I,Gejyo F,Nihei H,Nakamura Y

    更新日期:2002-03-01 00:00:00

  • BRCA2 T2722R is a deleterious allele that causes exon skipping.

    abstract::Patients with a strong family history of breast cancer are often counseled to receive genetic screening for BRCA1 and BRCA2 mutations, the strongest known predictors of breast cancer. A major limitation of genetic testing is the number of inconclusive results due to unclassified BRCA1 and BRCA2 sequence variants. Many...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/342192

    authors: Fackenthal JD,Cartegni L,Krainer AR,Olopade OI

    更新日期:2002-09-01 00:00:00

  • cDNA cloning and chromosomal localization (4q11-13) of a gene for statherin, a regulator of calcium in saliva.

    abstract::On the basis of the known amino acid sequence of statherin, a human salivary protein, mixed synthetic oligonucleotides were synthesized and used to screen a cDNA library constructed from human parotid-gland mRNA. A cDNA clone coding for statherin was isolated from this library and has been completely sequenced. The cD...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Sabatini LM,Carlock LR,Johnson GW,Azen EA

    更新日期:1987-12-01 00:00:00

  • Alzheimer disease: evidence for susceptibility loci on chromosomes 6 and 14.

    abstract::We report the transmission of HLA haplotypes and Gm allotypes in 97 members of a single kindred containing 257 individuals, 45 of whom were determined by clinical examination, autopsy, or historical data to have had Alzheimer disease (AD). Extensive inbreeding suggests that more than one gene may contribute to suscept...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Weitkamp LR,Nee L,Keats B,Polinsky RJ,Guttormsen S

    更新日期:1983-05-01 00:00:00

  • Leaky splicing mutation in the acid maltase gene is associated with delayed onset of glycogenosis type II.

    abstract::An autosomal recessive deficiency of acid alpha-glucosidase (GAA), type II glycogenosis, is genetically and clinically heterogeneous. The discovery of an enzyme-inactivating genomic deletion of exon 18 in three unrelated genetic compound patients--two infants and an adult--provided a rare opportunity to analyze the ef...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Boerkoel CF,Exelbert R,Nicastri C,Nichols RC,Miller FW,Plotz PH,Raben N

    更新日期:1995-04-01 00:00:00

  • How rapidly does the human mitochondrial genome evolve?

    abstract::The results of an empirical nucleotide-sequencing approach indicate that the evolution of the human mitochondrial noncoding D-loop is both more rapid and more complex than is revealed by standard phylogenetic approaches. The nucleotide sequence of the D-loop region of the mitochondrial genome was determined for 45 mem...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Howell N,Kubacka I,Mackey DA

    更新日期:1996-09-01 00:00:00

  • Multipoint genetic mapping with uniparental disomy data.

    abstract::Uniparental disomy (UPD) refers to the presence of two copies of a chromosome from one parent and none from the other parent. In genetic studies of UPDs, many genetic markers are usually used to identify the stage of nondisjunction that leads to UPD and to uncover the associated unusual patterns of recombinations. How...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/303072

    authors: Zhao H,Li J,Robinson WP

    更新日期:2000-10-01 00:00:00

  • Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval.

    abstract::Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic r...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2020.04.009

    authors: Ramírez J,van Duijvenboden S,Young WJ,Orini M,Lambiase PD,Munroe PB,Tinker A

    更新日期:2020-06-04 00:00:00

  • Phylogenetic and familial estimates of mitochondrial substitution rates: study of control region mutations in deep-rooting pedigrees.

    abstract::We studied mutations in the mtDNA control region (CR) using deep-rooting French-Canadian pedigrees. In 508 maternal transmissions, we observed four substitutions (0.0079 per generation per 673 bp, 95% CI 0.0023-0.186). Combined with other familial studies, our results add up to 18 substitutions in 1,729 transmissions ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/324024

    authors: Heyer E,Zietkiewicz E,Rochowski A,Yotova V,Puymirat J,Labuda D

    更新日期:2001-11-01 00:00:00

  • Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

    abstract::Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and i...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2020.07.006

    authors: Thomas M,Sakoda LC,Hoffmeister M,Rosenthal EA,Lee JK,van Duijnhoven FJB,Platz EA,Wu AH,Dampier CH,de la Chapelle A,Wolk A,Joshi AD,Burnett-Hartman A,Gsur A,Lindblom A,Castells A,Win AK,Namjou B,Van Guelpen B,Tangen

    更新日期:2020-09-03 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

  • Recent developments in genomewide association scans: a workshop summary and review.

    abstract::With the imminent availability of ultra-high-volume genotyping platforms (on the order of 100,000-1,000,000 genotypes per sample) at a manageable cost, there is growing interest in the possibility of conducting genomewide association studies for a variety of diseases but, so far, little consensus on methods to design ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,评审

    doi:10.1086/432962

    authors: Thomas DC,Haile RW,Duggan D

    更新日期:2005-09-01 00:00:00

  • Allele-Specific QTL Fine Mapping with PLASMA.

    abstract::Although quantitative trait locus (QTL) associations have been identified for many molecular traits such as gene expression, it remains challenging to distinguish the causal nucleotide from nearby variants. In addition to traditional QTLs by association, allele-specific (AS) QTLs are a powerful measure of cis-regulati...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2019.12.011

    authors: Wang AT,Shetty A,O'Connor E,Bell C,Pomerantz MM,Freedman ML,Gusev A

    更新日期:2020-02-06 00:00:00

  • MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population.

    abstract::Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% of all colorectal cancer (CRC) cases and is the most common hereditary CRC syndrome. We have previously reported a high incidence of microsatellite instability (MSI) and germline mismatch repair (MMR) gene mutations in young Hong Kong Chin...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/383591

    authors: Chan TL,Chan YW,Ho JW,Chan C,Chan AS,Chan E,Lam PW,Tse CW,Lee KC,Lau CW,Gwi E,Leung SY,Yuen ST

    更新日期:2004-05-01 00:00:00

  • Multipoint interval mapping of quantitative trait loci, using sib pairs.

    abstract::The sib-pair interval-mapping procedure of Fulker and Cardon is extended to take account of all available marker information on a chromosome simultaneously. The method provides a computationally fast multipoint analysis of sib-pair data, using a modified Haseman-Elston approach. It gives results very similar to those ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Fulker DW,Cherny SS,Cardon LR

    更新日期:1995-05-01 00:00:00