EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder.
EFEMP1
haploinsufficiency
hereditary connective tissue disorder
nonsense-mediated decay
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
13 Feb 2024
13 Feb 2024
Historique:
revised:
25
11
2023
received:
10
09
2023
accepted:
20
01
2024
medline:
13
2
2024
pubmed:
13
2
2024
entrez:
13
2
2024
Statut:
aheadofprint
Résumé
Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.
Identifiants
pubmed: 38348595
doi: 10.1002/ajmg.a.63556
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e63556Subventions
Organisme : NIH Common Fund
ID : 1U01HG010230
Investigateurs
Maria T Acosta
(MT)
Margaret Adam
(M)
David R Adams
(DR)
Pankaj B Agrawal
(PB)
Mercedes E Alejandro
(ME)
Justin Alvey
(J)
Laura Amendola
(L)
Ashley Andrews
(A)
Euan A Ashley
(EA)
Mahshid S Azamian
(MS)
Carlos A Bacino
(CA)
Guney Bademci
(G)
Eva Baker
(E)
Ashok Balasubramanyam
(A)
Dustin Baldridge
(D)
Jim Bale
(J)
Michael Bamshad
(M)
Deborah Barbouth
(D)
Pinar Bayrak-Toydemir
(P)
Anita Beck
(A)
Alan H Beggs
(AH)
Edward Behrens
(E)
Gill Bejerano
(G)
Jimmy Bennet
(J)
Beverly Berg-Rood
(B)
Jonathan A Bernstein
(JA)
Gerard T Berry
(GT)
Anna Bican
(A)
Stephanie Bivona
(S)
Elizabeth Blue
(E)
John Bohnsack
(J)
Carsten Bonnenmann
(C)
Devon Bonner
(D)
Lorenzo Botto
(L)
Brenna Boyd
(B)
Lauren C Briere
(LC)
Elly Brokamp
(E)
Gabrielle Brown
(G)
Elizabeth A Burke
(EA)
Lindsay C Burrage
(LC)
Manish J Butte
(MJ)
Peter Byers
(P)
William E Byrd
(WE)
John Carey
(J)
Olveen Carrasquillo
(O)
Ta Chen Peter Chang
(TCP)
Sirisak Chanprasert
(S)
Hsiao-Tuan Chao
(HT)
Gary D Clark
(GD)
Terra R Coakley
(TR)
Laurel A Cobban
(LA)
Joy D Cogan
(JD)
Matthew Coggins
(M)
F Sessions Cole
(FS)
Heather A Colley
(HA)
Cynthia M Cooper
(CM)
Heidi Cope
(H)
William J Craigen
(WJ)
Andrew B Crouse
(AB)
Michael Cunningham
(M)
Precilla D'Souza
(P)
Hongzheng Dai
(H)
Surendra Dasari
(S)
Joie Davis
(J)
Jyoti G Dayal
(JG)
Matthew Deardorff
(M)
Esteban C Dell'Angelica
(EC)
Shweta U Dhar
(SU)
Katrina Dipple
(K)
Daniel Doherty
(D)
Naghmeh Dorrani
(N)
Argenia L Doss
(AL)
Emilie D Douine
(ED)
David D Draper
(DD)
Laura Duncan
(L)
Dawn Earl
(D)
David J Eckstein
(DJ)
Lisa T Emrick
(LT)
Christine M Eng
(CM)
Cecilia Esteves
(C)
Marni Falk
(M)
Liliana Fernandez
(L)
Carlos Ferreira
(C)
Elizabeth L Fieg
(EL)
Laurie C Findley
(LC)
Paul G Fisher
(PG)
Brent L Fogel
(BL)
Irman Forghani
(I)
Laure Fresard
(L)
William A Gahl
(WA)
Ian Glass
(I)
Bernadette Gochuico
(B)
Rena A Godfrey
(RA)
Katie Golden-Grant
(K)
Alica M Goldman
(AM)
Madison P Goldrich
(MP)
David B Goldstein
(DB)
Alana Grajewski
(A)
Catherine A Groden
(CA)
Irma Gutierrez
(I)
Sihoun Hahn
(S)
Rizwan Hamid
(R)
Neil A Hanchard
(NA)
Kelly Hassey
(K)
Nichole Hayes
(N)
Frances High
(F)
Anne Hing
(A)
Fuki M Hisama
(FM)
Ingrid A Holm
(IA)
Jason Hom
(J)
Martha Horike-Pyne
(M)
Alden Huang
(A)
Yong Huang
(Y)
Laryssa Huryn
(L)
Rosario Isasi
(R)
Fariha Jamal
(F)
Gail P Jarvik
(GP)
Jeffrey Jarvik
(J)
Suman Jayadev
(S)
Lefkothea Karaviti
(L)
Jennifer Kennedy
(J)
Dana Kiley
(D)
Shilpa N Kobren
(SN)
Isaac S Kohane
(IS)
Jennefer N Kohler
(JN)
Deborah Krakow
(D)
Donna M Krasnewich
(DM)
Elijah Kravets
(E)
Susan Korrick
(S)
Mary Koziura
(M)
Joel B Krier
(JB)
Seema R Lalani
(SR)
Byron Lam
(B)
Christina Lam
(C)
Grace L LaMoure
(GL)
Brendan C Lanpher
(BC)
Ian R Lanza
(IR)
Lea Latham
(L)
Kimberly LeBlanc
(K)
Brendan H Lee
(BH)
Hane Lee
(H)
Roy Levitt
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Richard A Lewis
(RA)
Sharyn A Lincoln
(SA)
Pengfei Liu
(P)
Xue Zhong Liu
(XZ)
Nicola Longo
(N)
Sandra K Loo
(SK)
Joseph Loscalzo
(J)
Richard L Maas
(RL)
John MacDowall
(J)
Ellen F Macnamara
(EF)
Calum A MacRae
(CA)
Valerie V Maduro
(VV)
Marta M Majcherska
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Bryan C Mak
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May Christine V Malicdan
(MCV)
Laura A Mamounas
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Teri A Manolio
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Rong Mao
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Kenneth Maravilla
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Thomas C Markello
(TC)
Ronit Marom
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Gabor Marth
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Beth A Martin
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Martin G Martin
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Julian A Martínez-Agosto
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Shruti Marwaha
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Jacob McCauley
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Allyn McConkie-Rosell
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Colleen E McCormack
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Alexa T McCray
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Elisabeth McGee
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Heather Mefford
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J Lawrence Merritt
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Matthew Might
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Ghayda Mirzaa
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Eva Morava
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Paolo M Moretti
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Deborah Mosbrook-Davis
(D)
John J Mulvihill
(JJ)
David R Murdock
(DR)
Anna Nagy
(A)
Mariko Nakano-Okuno
(M)
Avi Nath
(A)
Stan F Nelson
(SF)
John H Newman
(JH)
Sarah K Nicholas
(SK)
Deborah Nickerson
(D)
Shirley Nieves-Rodriguez
(S)
Donna Novacic
(D)
Devin Oglesbee
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James P Orengo
(JP)
Laura Pace
(L)
Stephen C Pak
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J Carl Pallais
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Neil H Parker
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Genecee Renteria
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Chloe M Reuter
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Lynette Rives
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Amy K Robertson
(AK)
Lance H Rodan
(LH)
Jill A Rosenfeld
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Natalie Rosenwasser
(N)
Francis Rossignol
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Maura Ruzhnikov
(M)
Ralph Sacco
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Jacinda B Sampson
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Susan L Samson
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C Ron Scott
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Judy Schaechter
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Kelly Schoch
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Daryl A Scott
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Vandana Shashi
(V)
Jimann Shin
(J)
Rebecca Signer
(R)
Edwin K Silverman
(EK)
Janet S Sinsheimer
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Kathy Sisco
(K)
Edward C Smith
(EC)
Kevin S Smith
(KS)
Emily Solem
(E)
Lilianna Solnica-Krezel
(L)
Ben Solomon
(B)
Rebecca C Spillmann
(RC)
Joan M Stoler
(JM)
Jennifer A Sullivan
(JA)
Kathleen Sullivan
(K)
Angela Sun
(A)
Shirley Sutton
(S)
David A Sweetser
(DA)
Virginia Sybert
(V)
Holly K Tabor
(HK)
Amelia L M Tan
(ALM)
Queenie K-G Tan
(QK)
Mustafa Tekin
(M)
Fred Telischi
(F)
Willa Thorson
(W)
Audrey Thurm
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Cynthia J Tifft
(CJ)
Camilo Toro
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Alyssa A Tran
(AA)
Brianna M Tucker
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Tiina K Urv
(TK)
Adeline Vanderver
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(NM)
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(C)
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(S)
Informations de copyright
© 2024 Wiley Periodicals LLC.
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