Compound heterozygous mutations in FBN1 in a large family with Marfan syndrome
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc..
BACKGROUND: Marfan syndrome (MFS) is a dominant monogenic disorder caused by mutations in fibrillin 1 (FBN1). Rarely, compound heterozygosity for FBN1 mutations has been described.
METHODS: A large kindred with MFS was assessed clinically over decades, and genetically using exome and/or Sanger sequencing.
RESULTS: A previously identified FBN1 missense variant (p.Tyr754Cys) was confirmed in all subjects with MFS. An additional variant (p.Met2273Thr), previously associated with incomplete MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years. In contrast, their heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair.
CONCLUSION: Although compound heterozygosity or homozygosity is rare in MFS, it should be considered when there is an unusually severe phenotype in a subset of family members.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
Molecular genetics & genomic medicine - 8(2020), 3 vom: 09. März, Seite e1116 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
McInerney-Leo, Aideen M [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Case Reports |
|---|
| Anmerkungen: |
Date Completed 29.03.2021 Date Revised 29.03.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1002/mgg3.1116 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM305489534 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM305489534 | ||
| 003 | DE-627 | ||
| 005 | 20231225121308.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/mgg3.1116 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1018.xml |
| 035 | |a (DE-627)NLM305489534 | ||
| 035 | |a (NLM)31950671 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a McInerney-Leo, Aideen M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Compound heterozygous mutations in FBN1 in a large family with Marfan syndrome |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.03.2021 | ||
| 500 | |a Date Revised 29.03.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. | ||
| 520 | |a BACKGROUND: Marfan syndrome (MFS) is a dominant monogenic disorder caused by mutations in fibrillin 1 (FBN1). Rarely, compound heterozygosity for FBN1 mutations has been described | ||
| 520 | |a METHODS: A large kindred with MFS was assessed clinically over decades, and genetically using exome and/or Sanger sequencing | ||
| 520 | |a RESULTS: A previously identified FBN1 missense variant (p.Tyr754Cys) was confirmed in all subjects with MFS. An additional variant (p.Met2273Thr), previously associated with incomplete MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years. In contrast, their heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair | ||
| 520 | |a CONCLUSION: Although compound heterozygosity or homozygosity is rare in MFS, it should be considered when there is an unusually severe phenotype in a subset of family members | ||
| 650 | 4 | |a Case Reports | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a FBN1 | |
| 650 | 4 | |a fibrillin 1 | |
| 650 | 4 | |a Marfan syndrome | |
| 650 | 4 | |a compound heterozygous | |
| 650 | 7 | |a FBN1 protein, human |2 NLM | |
| 650 | 7 | |a Fibrillin-1 |2 NLM | |
| 700 | 1 | |a West, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Wheeler, Lawrie |e verfasserin |4 aut | |
| 700 | 1 | |a Leo, Paul J |e verfasserin |4 aut | |
| 700 | 1 | |a Summers, Kim M |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Matthew A |e verfasserin |4 aut | |
| 700 | 1 | |a West, Malcolm |e verfasserin |4 aut | |
| 700 | 1 | |a Duncan, Emma L |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular genetics & genomic medicine |d 2013 |g 8(2020), 3 vom: 09. März, Seite e1116 |w (DE-627)NLM229947956 |x 2324-9269 |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2020 |g number:3 |g day:09 |g month:03 |g pages:e1116 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/mgg3.1116 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2020 |e 3 |b 09 |c 03 |h e1116 | ||