EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder

Undiagnosed Diseases Network; Irman Forghani; Steven H. Lang; Matthew J. Rodier; Stephanie A. Bivona; Maria T. Acosta; Margaret Adam; David R. Adams; Pankaj B. Agrawal; Mercedes E. Alejandro; Justin Alvey; Laura Amendola; Ashley Andrews; Euan A. Ashley; Mahshid S. Azamian; Carlos A. Bacino; Guney Bademci; Eva Baker; Ashok Balasubramanyam; Dustin Baldridge; Jim Bale; Michael Bamshad; Deborah Barbouth; Pinar Bayrak-Toydemir; Anita Beck; Alan H. Beggs; Edward Behrens; Gill Bejerano; Jimmy Bennet; Beverly Berg-Rood; Jonathan A. Bernstein; Gerard T. Berry; Anna Bican; Stephanie Bivona; Elizabeth Blue; John Bohnsack; Carsten Bonnenmann; Devon Bonner; Lorenzo Botto; Brenna Boyd; Lauren C. Briere; Elly Brokamp; Gabrielle Brown; Elizabeth A. Burke; Lindsay C. Burrage; Manish J. Butte; Peter Byers; William E. Byrd; John Carey; Olveen Carrasquillo; Ta Chen Peter Chang; Sirisak Chanprasert; Hsiao Tuan Chao; Gary D. Clark; Terra R. Coakley; Laurel A. Cobban; Joy D. Cogan; Matthew Coggins; F. Sessions Cole; Heather A. Colley; Cynthia M. Cooper; Heidi Cope; William J. Craigen; Andrew B. Crouse; Michael Cunningham; Precilla D'Souza; Hongzheng Dai; Surendra Dasari; Joie Davis; Jyoti G. Dayal; Matthew Deardorff; Esteban C. Dell'Angelica; Shweta U. Dhar; Katrina Dipple; Daniel Doherty; Naghmeh Dorrani; Argenia L. Doss; Emilie D. Douine; David D. Draper; Laura Duncan; Dawn Earl; David J. Eckstein; Lisa T. Emrick; Christine M. Eng; Cecilia Esteves; Marni Falk; Liliana Fernandez; Carlos Ferreira; Elizabeth L. Fieg; Laurie C. Findley; Paul G. Fisher; Brent L. Fogel; Irman Forghani; Laure Fresard; William A. Gahl; Ian Glass; Bernadette Gochuico; Rena A. Godfrey; Katie Golden-Grant; Alica M. Goldman; Madison P. Goldrich; David B. Goldstein; Alana Grajewski; Catherine A. Groden; Irma Gutierrez; Sihoun Hahn; Rizwan Hamid; Neil A. Hanchard; Kelly Hassey; Nichole Hayes; Frances High; Anne Hing; Fuki M. Hisama; Ingrid A. Holm; Jason Hom; Martha Horike-Pyne; Alden Huang; Yong Huang; Laryssa Huryn; Rosario Isasi; Fariha Jamal; Gail P. Jarvik; Jeffrey Jarvik; Suman Jayadev; Lefkothea Karaviti; Jennifer Kennedy; Dana Kiley; Shilpa N. Kobren; Isaac S. Kohane; Jennefer N. Kohler; Deborah Krakow; Donna M. Krasnewich; Elijah Kravets; Susan Korrick; Mary Koziura; Joel B. Krier; Seema R. Lalani; Byron Lam; Christina Lam; Grace L. LaMoure; Brendan C. Lanpher; Ian R. Lanza; Lea Latham; Kimberly LeBlanc; Brendan H. Lee; Hane Lee; Roy Levitt; Richard A. Lewis; Sharyn A. Lincoln; Pengfei Liu; Xue Zhong Liu; Nicola Longo; Sandra K. Loo; Joseph Loscalzo; Richard L. Maas; John MacDowall; Ellen F. Macnamara; Calum A. MacRae; Valerie V. Maduro; Marta M. Majcherska; Bryan C. Mak; May Christine V. Malicdan; Laura A. Mamounas; Teri A. Manolio; Rong Mao; Kenneth Maravilla; Thomas C. Markello; Ronit Marom; Gabor Marth; Beth A. Martin; Martin G. Martin; Julian A. Martínez-Agosto; Shruti Marwaha; Jacob McCauley; Allyn McConkie-Rosell; Colleen E. McCormack; Alexa T. McCray; Elisabeth McGee; Heather Mefford; J. Lawrence Merritt; Matthew Might; Ghayda Mirzaa; Eva Morava; Paolo M. Moretti; Deborah Mosbrook-Davis; John J. Mulvihill; David R. Murdock; Anna Nagy; Mariko Nakano-Okuno; Avi Nath; Stan F. Nelson; John H. Newman; Sarah K. Nicholas; Deborah Nickerson; Shirley Nieves-Rodriguez; Donna Novacic; Stephen C. Pak; Timothy Schedl; Jimann Shin; Lilianna Solnica-Krezel; Jennifer Wambach

doi:10.1002/ajmg.a.63556

EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder

Undiagnosed Diseases Network, Irman Forghani, Steven H. Lang, Matthew J. Rodier, Stephanie A. Bivona, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin BaldridgeJim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell'Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Stephen C. Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Jennifer Wambach

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English
Article number	e63556
Journal	American Journal of Medical Genetics, Part A
Volume	194
Issue number	6
DOIs	https://doi.org/10.1002/ajmg.a.63556
State	Published - Jun 2024

Keywords

EFEMP1
haploinsufficiency
hereditary connective tissue disorder
nonsense-mediated decay

Access to Document

10.1002/ajmg.a.63556

Cite this

Undiagnosed Diseases Network, Forghani, I., Lang, S. H., Rodier, M. J., Bivona, S. A., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., ... Wambach, J. (2024). EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder. American Journal of Medical Genetics, Part A, 194(6), Article e63556. https://doi.org/10.1002/ajmg.a.63556

@article{4e34131c85664eed8d2c139a61c66207,

title = "EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder",

abstract = "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.",

keywords = "EFEMP1, haploinsufficiency, hereditary connective tissue disorder, nonsense-mediated decay",

author = "{Undiagnosed Diseases Network} and Irman Forghani and Lang, {Steven H.} and Rodier, {Matthew J.} and Bivona, {Stephanie A.} and Acosta, {Maria T.} and Margaret Adam and Adams, {David R.} and Agrawal, {Pankaj B.} and Alejandro, {Mercedes E.} and Justin Alvey and Laura Amendola and Ashley Andrews and Ashley, {Euan A.} and Azamian, {Mahshid S.} and Bacino, {Carlos A.} and Guney Bademci and Eva Baker and Ashok Balasubramanyam and Dustin Baldridge and Jim Bale and Michael Bamshad and Deborah Barbouth and Pinar Bayrak-Toydemir and Anita Beck and Beggs, {Alan H.} and Edward Behrens and Gill Bejerano and Jimmy Bennet and Beverly Berg-Rood and Bernstein, {Jonathan A.} and Berry, {Gerard T.} and Anna Bican and Stephanie Bivona and Elizabeth Blue and John Bohnsack and Carsten Bonnenmann and Devon Bonner and Lorenzo Botto and Brenna Boyd and Briere, {Lauren C.} and Elly Brokamp and Gabrielle Brown and Burke, {Elizabeth A.} and Burrage, {Lindsay C.} and Butte, {Manish J.} and Peter Byers and Byrd, {William E.} and John Carey and Olveen Carrasquillo and Chang, {Ta Chen Peter} and Sirisak Chanprasert and Chao, {Hsiao Tuan} and Clark, {Gary D.} and Coakley, {Terra R.} and Cobban, {Laurel A.} and Cogan, {Joy D.} and Matthew Coggins and Cole, {F. Sessions} and Colley, {Heather A.} and Cooper, {Cynthia M.} and Heidi Cope and Craigen, {William J.} and Crouse, {Andrew B.} and Michael Cunningham and Precilla D'Souza and Hongzheng Dai and Surendra Dasari and Joie Davis and Dayal, {Jyoti G.} and Matthew Deardorff and Dell'Angelica, {Esteban C.} and Dhar, {Shweta U.} and Katrina Dipple and Daniel Doherty and Naghmeh Dorrani and Doss, {Argenia L.} and Douine, {Emilie D.} and Draper, {David D.} and Laura Duncan and Dawn Earl and Eckstein, {David J.} and Emrick, {Lisa T.} and Eng, {Christine M.} and Cecilia Esteves and Marni Falk and Liliana Fernandez and Carlos Ferreira and Fieg, {Elizabeth L.} and Findley, {Laurie C.} and Fisher, {Paul G.} and Fogel, {Brent L.} and Irman Forghani and Laure Fresard and Gahl, {William A.} and Ian Glass and Bernadette Gochuico and Godfrey, {Rena A.} and Katie Golden-Grant and Goldman, {Alica M.} and Goldrich, {Madison P.} and Goldstein, {David B.} and Alana Grajewski and Groden, {Catherine A.} and Irma Gutierrez and Sihoun Hahn and Rizwan Hamid and Hanchard, {Neil A.} and Kelly Hassey and Nichole Hayes and Frances High and Anne Hing and Hisama, {Fuki M.} and Holm, {Ingrid A.} and Jason Hom and Martha Horike-Pyne and Alden Huang and Yong Huang and Laryssa Huryn and Rosario Isasi and Fariha Jamal and Jarvik, {Gail P.} and Jeffrey Jarvik and Suman Jayadev and Lefkothea Karaviti and Jennifer Kennedy and Dana Kiley and Kobren, {Shilpa N.} and Kohane, {Isaac S.} and Kohler, {Jennefer N.} and Deborah Krakow and Krasnewich, {Donna M.} and Elijah Kravets and Susan Korrick and Mary Koziura and Krier, {Joel B.} and Lalani, {Seema R.} and Byron Lam and Christina Lam and LaMoure, {Grace L.} and Lanpher, {Brendan C.} and Lanza, {Ian R.} and Lea Latham and Kimberly LeBlanc and Lee, {Brendan H.} and Hane Lee and Roy Levitt and Lewis, {Richard A.} and Lincoln, {Sharyn A.} and Pengfei Liu and Liu, {Xue Zhong} and Nicola Longo and Loo, {Sandra K.} and Joseph Loscalzo and Maas, {Richard L.} and John MacDowall and Macnamara, {Ellen F.} and MacRae, {Calum A.} and Maduro, {Valerie V.} and Majcherska, {Marta M.} and Mak, {Bryan C.} and Malicdan, {May Christine V.} and Mamounas, {Laura A.} and Manolio, {Teri A.} and Rong Mao and Kenneth Maravilla and Markello, {Thomas C.} and Ronit Marom and Gabor Marth and Martin, {Beth A.} and Martin, {Martin G.} and Mart{\'i}nez-Agosto, {Julian A.} and Shruti Marwaha and Jacob McCauley and Allyn McConkie-Rosell and McCormack, {Colleen E.} and McCray, {Alexa T.} and Elisabeth McGee and Heather Mefford and Merritt, {J. Lawrence} and Matthew Might and Ghayda Mirzaa and Eva Morava and Moretti, {Paolo M.} and Deborah Mosbrook-Davis and Mulvihill, {John J.} and Murdock, {David R.} and Anna Nagy and Mariko Nakano-Okuno and Avi Nath and Nelson, {Stan F.} and Newman, {John H.} and Nicholas, {Sarah K.} and Deborah Nickerson and Shirley Nieves-Rodriguez and Donna Novacic and Pak, {Stephen C.} and Timothy Schedl and Jimann Shin and Lilianna Solnica-Krezel and Jennifer Wambach",

note = "Publisher Copyright: {\textcopyright} 2024 Wiley Periodicals LLC.",

year = "2024",

month = jun,

doi = "10.1002/ajmg.a.63556",

language = "English",

volume = "194",

journal = "American Journal of Medical Genetics, Part A",

issn = "1552-4825",

number = "6",

}

Undiagnosed Diseases Network, Forghani, I, Lang, SH, Rodier, MJ, Bivona, SA, Acosta, MT, Adam, M, Adams, DR, Agrawal, PB, Alejandro, ME, Alvey, J, Amendola, L, Andrews, A, Ashley, EA, Azamian, MS, Bacino, CA, Bademci, G, Baker, E, Balasubramanyam, A, Baldridge, D, Bale, J, Bamshad, M, Barbouth, D, Bayrak-Toydemir, P, Beck, A, Beggs, AH, Behrens, E, Bejerano, G, Bennet, J, Berg-Rood, B, Bernstein, JA, Berry, GT, Bican, A, Bivona, S, Blue, E, Bohnsack, J, Bonnenmann, C, Bonner, D, Botto, L, Boyd, B, Briere, LC, Brokamp, E, Brown, G, Burke, EA, Burrage, LC, Butte, MJ, Byers, P, Byrd, WE, Carey, J, Carrasquillo, O, Chang, TCP, Chanprasert, S, Chao, HT, Clark, GD, Coakley, TR, Cobban, LA, Cogan, JD, Coggins, M, Cole, FS, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, Crouse, AB, Cunningham, M, D'Souza, P, Dai, H, Dasari, S, Davis, J, Dayal, JG, Deardorff, M, Dell'Angelica, EC, Dhar, SU, Dipple, K, Doherty, D, Dorrani, N, Doss, AL, Douine, ED, Draper, DD, Duncan, L, Earl, D, Eckstein, DJ, Emrick, LT, Eng, CM, Esteves, C, Falk, M, Fernandez, L, Ferreira, C, Fieg, EL, Findley, LC, Fisher, PG, Fogel, BL, Forghani, I, Fresard, L, Gahl, WA, Glass, I, Gochuico, B, Godfrey, RA, Golden-Grant, K, Goldman, AM, Goldrich, MP, Goldstein, DB, Grajewski, A, Groden, CA, Gutierrez, I, Hahn, S, Hamid, R, Hanchard, NA, Hassey, K, Hayes, N, High, F, Hing, A, Hisama, FM, Holm, IA, Hom, J, Horike-Pyne, M, Huang, A, Huang, Y, Huryn, L, Isasi, R, Jamal, F, Jarvik, GP, Jarvik, J, Jayadev, S, Karaviti, L, Kennedy, J, Kiley, D, Kobren, SN, Kohane, IS, Kohler, JN, Krakow, D, Krasnewich, DM, Kravets, E, Korrick, S, Koziura, M, Krier, JB, Lalani, SR, Lam, B, Lam, C, LaMoure, GL, Lanpher, BC, Lanza, IR, Latham, L, LeBlanc, K, Lee, BH, Lee, H, Levitt, R, Lewis, RA, Lincoln, SA, Liu, P, Liu, XZ, Longo, N, Loo, SK, Loscalzo, J, Maas, RL, MacDowall, J, Macnamara, EF, MacRae, CA, Maduro, VV, Majcherska, MM, Mak, BC, Malicdan, MCV, Mamounas, LA, Manolio, TA, Mao, R, Maravilla, K, Markello, TC, Marom, R, Marth, G, Martin, BA, Martin, MG, Martínez-Agosto, JA, Marwaha, S, McCauley, J, McConkie-Rosell, A, McCormack, CE, McCray, AT, McGee, E, Mefford, H, Merritt, JL, Might, M, Mirzaa, G, Morava, E, Moretti, PM, Mosbrook-Davis, D, Mulvihill, JJ, Murdock, DR, Nagy, A, Nakano-Okuno, M, Nath, A, Nelson, SF, Newman, JH, Nicholas, SK, Nickerson, D, Nieves-Rodriguez, S, Novacic, D, Pak, SC , Schedl, T , Shin, J , Solnica-Krezel, L & Wambach, J 2024, 'EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder', American Journal of Medical Genetics, Part A, vol. 194, no. 6, e63556. https://doi.org/10.1002/ajmg.a.63556

TY - JOUR

T1 - EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder

AU - Undiagnosed Diseases Network

AU - Forghani, Irman

AU - Lang, Steven H.

AU - Rodier, Matthew J.

AU - Bivona, Stephanie A.

AU - Acosta, Maria T.

AU - Adam, Margaret

AU - Adams, David R.

AU - Agrawal, Pankaj B.

AU - Alejandro, Mercedes E.

AU - Alvey, Justin

AU - Amendola, Laura

AU - Andrews, Ashley

AU - Ashley, Euan A.

AU - Azamian, Mahshid S.

AU - Bacino, Carlos A.

AU - Bademci, Guney

AU - Baker, Eva

AU - Balasubramanyam, Ashok

AU - Baldridge, Dustin

AU - Bale, Jim

AU - Bamshad, Michael

AU - Barbouth, Deborah

AU - Bayrak-Toydemir, Pinar

AU - Beck, Anita

AU - Beggs, Alan H.

AU - Behrens, Edward

AU - Bejerano, Gill

AU - Bennet, Jimmy

AU - Berg-Rood, Beverly

AU - Bernstein, Jonathan A.

AU - Berry, Gerard T.

AU - Bican, Anna

AU - Bivona, Stephanie

AU - Blue, Elizabeth

AU - Bohnsack, John

AU - Bonnenmann, Carsten

AU - Bonner, Devon

AU - Botto, Lorenzo

AU - Boyd, Brenna

AU - Briere, Lauren C.

AU - Brokamp, Elly

AU - Brown, Gabrielle

AU - Burke, Elizabeth A.

AU - Burrage, Lindsay C.

AU - Butte, Manish J.

AU - Byers, Peter

AU - Byrd, William E.

AU - Carey, John

AU - Carrasquillo, Olveen

AU - Chang, Ta Chen Peter

AU - Chanprasert, Sirisak

AU - Chao, Hsiao Tuan

AU - Clark, Gary D.

AU - Coakley, Terra R.

AU - Cobban, Laurel A.

AU - Cogan, Joy D.

AU - Coggins, Matthew

AU - Cole, F. Sessions

AU - Colley, Heather A.

AU - Cooper, Cynthia M.

AU - Cope, Heidi

AU - Craigen, William J.

AU - Crouse, Andrew B.

AU - Cunningham, Michael

AU - D'Souza, Precilla

AU - Dai, Hongzheng

AU - Dasari, Surendra

AU - Davis, Joie

AU - Dayal, Jyoti G.

AU - Deardorff, Matthew

AU - Dell'Angelica, Esteban C.

AU - Dhar, Shweta U.

AU - Dipple, Katrina

AU - Doherty, Daniel

AU - Dorrani, Naghmeh

AU - Doss, Argenia L.

AU - Douine, Emilie D.

AU - Draper, David D.

AU - Duncan, Laura

AU - Earl, Dawn

AU - Eckstein, David J.

AU - Emrick, Lisa T.

AU - Eng, Christine M.

AU - Esteves, Cecilia

AU - Falk, Marni

AU - Fernandez, Liliana

AU - Ferreira, Carlos

AU - Fieg, Elizabeth L.

AU - Findley, Laurie C.

AU - Fisher, Paul G.

AU - Fogel, Brent L.

AU - Forghani, Irman

AU - Fresard, Laure

AU - Gahl, William A.

AU - Glass, Ian

AU - Gochuico, Bernadette

AU - Godfrey, Rena A.

AU - Golden-Grant, Katie

AU - Goldman, Alica M.

AU - Goldrich, Madison P.

AU - Goldstein, David B.

AU - Grajewski, Alana

AU - Groden, Catherine A.

AU - Gutierrez, Irma

AU - Hahn, Sihoun

AU - Hamid, Rizwan

AU - Hanchard, Neil A.

AU - Hassey, Kelly

AU - Hayes, Nichole

AU - High, Frances

AU - Hing, Anne

AU - Hisama, Fuki M.

AU - Holm, Ingrid A.

AU - Hom, Jason

AU - Horike-Pyne, Martha

AU - Huang, Alden

AU - Huang, Yong

AU - Huryn, Laryssa

AU - Isasi, Rosario

AU - Jamal, Fariha

AU - Jarvik, Gail P.

AU - Jarvik, Jeffrey

AU - Jayadev, Suman

AU - Karaviti, Lefkothea

AU - Kennedy, Jennifer

AU - Kiley, Dana

AU - Kobren, Shilpa N.

AU - Kohane, Isaac S.

AU - Kohler, Jennefer N.

AU - Krakow, Deborah

AU - Krasnewich, Donna M.

AU - Kravets, Elijah

AU - Korrick, Susan

AU - Koziura, Mary

AU - Krier, Joel B.

AU - Lalani, Seema R.

AU - Lam, Byron

AU - Lam, Christina

AU - LaMoure, Grace L.

AU - Lanpher, Brendan C.

AU - Lanza, Ian R.

AU - Latham, Lea

AU - LeBlanc, Kimberly

AU - Lee, Brendan H.

AU - Lee, Hane

AU - Levitt, Roy

AU - Lewis, Richard A.

AU - Lincoln, Sharyn A.

AU - Liu, Pengfei

AU - Liu, Xue Zhong

AU - Longo, Nicola

AU - Loo, Sandra K.

AU - Loscalzo, Joseph

AU - Maas, Richard L.

AU - MacDowall, John

AU - Macnamara, Ellen F.

AU - MacRae, Calum A.

AU - Maduro, Valerie V.

AU - Majcherska, Marta M.

AU - Mak, Bryan C.

AU - Malicdan, May Christine V.

AU - Mamounas, Laura A.

AU - Manolio, Teri A.

AU - Mao, Rong

AU - Maravilla, Kenneth

AU - Markello, Thomas C.

AU - Marom, Ronit

AU - Marth, Gabor

AU - Martin, Beth A.

AU - Martin, Martin G.

AU - Martínez-Agosto, Julian A.

AU - Marwaha, Shruti

AU - McCauley, Jacob

AU - McConkie-Rosell, Allyn

AU - McCormack, Colleen E.

AU - McCray, Alexa T.

AU - McGee, Elisabeth

AU - Mefford, Heather

AU - Merritt, J. Lawrence

AU - Might, Matthew

AU - Mirzaa, Ghayda

AU - Morava, Eva

AU - Moretti, Paolo M.

AU - Mosbrook-Davis, Deborah

AU - Mulvihill, John J.

AU - Murdock, David R.

AU - Nagy, Anna

AU - Nakano-Okuno, Mariko

AU - Nath, Avi

AU - Nelson, Stan F.

AU - Newman, John H.

AU - Nicholas, Sarah K.

AU - Nickerson, Deborah

AU - Nieves-Rodriguez, Shirley

AU - Novacic, Donna

AU - Pak, Stephen C.

AU - Schedl, Timothy

AU - Shin, Jimann

AU - Solnica-Krezel, Lilianna

AU - Wambach, Jennifer

PY - 2024/6

Y1 - 2024/6

N2 - 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.

AB - 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.

KW - EFEMP1

KW - haploinsufficiency

KW - hereditary connective tissue disorder

KW - nonsense-mediated decay

UR - http://www.scopus.com/inward/record.url?scp=85185676714&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.63556

DO - 10.1002/ajmg.a.63556

M3 - Article

C2 - 38348595

AN - SCOPUS:85185676714

SN - 1552-4825

VL - 194

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

IS - 6

M1 - e63556

ER -

EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder

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