Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

被引:97
作者
Koczkowska, Magdalena [1 ,74 ]
Callens, Tom [1 ]
Chen, Yunjia [1 ]
Gomes, Alicia [1 ]
Hicks, Alesha D. [1 ]
Sharp, Angela [1 ]
Johns, Eric [1 ]
Uhas, Kim Armfield [2 ]
Armstrong, Linlea [3 ]
Bosanko, Katherine Armstrong [4 ]
Babovic-Vuksanovic, Dusica [5 ]
Baker, Laura [6 ]
Basel, Donald G. [7 ]
Bengala, Mario [8 ]
Bennett, James T. [9 ]
Chambers, Chelsea [10 ]
Clarkson, Lola K. [11 ]
Clementi, Maurizio [12 ]
Cortes, Fanny M. [13 ]
Cunningham, Mitch [14 ]
D'Agostino, M. Daniela [15 ]
Delatycki, Martin B. [16 ]
Digilio, Maria C. [17 ]
Dosa, Laura [18 ]
Esposito, Silvia [19 ]
Fox, Stephanie [15 ]
Freckmann, Mary-Louise [20 ]
Fauth, Christine [21 ]
Giugliano, Teresa [22 ]
Giustini, Sandra [23 ]
Goetsch, Allison [24 ]
Goldberg, Yael [25 ]
Greenwood, Robert S. [26 ]
Griffis, Cristin [7 ]
Gripp, Karen W. [6 ]
Gupta, Punita [27 ]
Haan, Eric [28 ]
Hachen, Rachel K. [29 ]
Haygarth, Tamara L. [30 ]
Hernandez-Chico, Concepcion [31 ,32 ]
Hodge, Katelyn [33 ]
Hopkin, Robert J. [3 ]
Hudgins, Louanne [35 ]
Janssens, Sandra [36 ]
Keller, Kory [37 ]
Kelly-Mancuso, Geraldine [34 ]
Kochhar, Aaina [38 ]
Korf, Bruce R. [1 ]
Lewis, Andrea M. [39 ]
Liebelt, Jan [40 ]
机构
[1] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA
[2] Childrens Healthcare Atlanta Scottish Rite, Atlanta, GA USA
[3] Univ British Columbia, BC Womens Hosp, Dept Med Genet, Vancouver, BC, Canada
[4] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Div Clin Genet & Metab, Little Rock, AR 72205 USA
[5] Mayo Clin, Dept Clin Genom, Rochester, MN USA
[6] Alfred I DuPont Hosp Children, Div Med Genet, Wilmington, DE USA
[7] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA
[8] Fdn Policlin Tor Vergata, Dipartimento Oncoematol, UOC Lab Genet Med, Rome, Italy
[9] Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA
[10] Univ Virginia, Dept Neurol, Med Ctr, Charlottesville, VA USA
[11] Greenwood Genet Ctr, Greenwood, SC 29646 USA
[12] Univ Padua, Dept Womens & Childrens Hlth, Clin Genet Unit, Padua, Italy
[13] Clin Las Condes, Ctr Rare Dis, Santiago, Chile
[14] Childrens Hosp Michigan, Detroit Med Ctr, Div Genet Gen & Metab Disorders, Detroit, MI 48201 USA
[15] McGill Univ, Hlth Ctr, Div Med Genet, Montreal, PQ, Canada
[16] Murdoch Childrens Res Inst, Bruce Lefroy Ctr Genet Hlth Res, Parkville, Vic, Australia
[17] Bambino Gesu Pediat Hosp, IRCCS, Med Genet Unit, Rome, Italy
[18] AOU Meyer, SOC Genet Med, Florence, Italy
[19] Fdn IRCCS Ist Neurol Carlo Besta, Dev Neurol Unit, Milan, Italy
[20] Royal North Shore Hosp, Dept Clin Genet, St Leonards, NSW, Australia
[21] Med Univ Innsbruck, Div Human Genet, Innsbruck, Austria
[22] Univ Campania Luigi Vanvitelli, Dept Precis Med, Naples, Italy
[23] Sapienza Univ Rome, Policlin Umberto 1, Dept Dermatol & Venereol, Rome, Italy
[24] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA
[25] Rabin Med Ctr, Raphael Recanati Genet Inst, Petah Tiqwa, Israel
[26] Univ N Carolina, Sch Med, Div Child Neurol, Chapel Hill, NC 27515 USA
[27] St Josephs Childrens Hosp, Neurofibromatosis Diagnost & Treatment Program, Paterson, NJ USA
[28] Royal Adelaide Hosp, Adult Genet Unit, Adelaide, SA, Australia
[29] Childrens Hosp Philadelphia, Neurofibromatosis Program, Philadelphia, PA 19104 USA
[30] Levine Childrens Specialty Ctr, Carolinas HealthCare Syst, Charlotte, NC USA
[31] Hosp Univ Ramon & Cajal, Inst Hlth Res IRYCIS, Dept Genet, Madrid, Spain
[32] Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
[33] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA
[34] Cincinnati Childrens Hosp Med Ctr, Dept Human Genet, Cincinnati, OH 45229 USA
[35] Stanford Univ, Sch Med, Div Med Genet, Stanford, CA 94305 USA
[36] Ghent Univ Hosp, Ctr Med Genet, Ghent, Belgium
[37] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
[38] Valley Childrens Healthcare, Dept Med Genet & Metab, Madera, CA USA
[39] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[40] Womens & Childrens Hosp, South Australian Clin Genet Serv, Adelaide, SA, Australia
[41] IPG, Ctr Human Genet, Gosselies, Belgium
[42] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA
[43] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Human Genet, Philadelphia, PA 19104 USA
[44] Univ Naples Federico II, Dept Translat Med Sci, Sect Pediat, Naples, Italy
[45] Childrens Hosp Minnesota, Genom Med Program, Minneapolis, MN USA
[46] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada
[47] Univ Iowa, Stead Family Childrens Hosp, Iowa City, IA USA
[48] NYU, Sch Med, Dept Pediat, Div Clin Genet Serv, New York, NY USA
[49] Univ Minnesota, Dept Pediat & Opthalmol, Minneapolis, MN USA
[50] IRCCS Casa Sollievo Sofferenza, Mol Genet Unit, Foggia, Italy
关键词
genotype-phenotype correlation; NF1; p; Arg1276; Lys1423; Met1149; OPTIC PATHWAY TUMORS; SOUTH EAST WALES; AU-LAIT SPOTS; NOONAN-SYNDROME; VONRECKLINGHAUSEN NEUROFIBROMATOSIS; SPINAL NEUROFIBROMATOSIS; PULMONARY STENOSIS; NATURAL-HISTORY; INDEPENDENT NF1; MUTATIONS;
D O I
10.1002/humu.23929
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
引用
收藏
页码:299 / 315
页数:17
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