Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes

Philip F. Giampietro, Linlea Armstrong, Alex Stoddard, Robert D. Blank, Janet Livingston, Cathy L. Raggio, Kristen Rasmussen, Michael Pickart, Rachel Lorier, Amy Turner, Sarah Sund, Nara Sobrera, Enid Neptune, David Sweetser, Alberto Santiago-Cornier, Ulrich Broeckel

Research output: Contribution to journalArticle

Abstract

We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.

Original languageEnglish (US)
Pages (from-to)95-102
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume167
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Klippel-Feil Syndrome
Mandibulofacial Dysostosis
Exome
Nuclear Family
Fathers
Mutation
RNA Polymerase I
External Ear
Aptitude
Genetic Heterogeneity
RNA Polymerase II
Delayed Diagnosis
Cleft Palate
Neck

Keywords

  • Autosomal dominant
  • Klippel-Feil
  • Treacher Collins syndrome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Medicine(all)

Cite this

Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes. / Giampietro, Philip F.; Armstrong, Linlea; Stoddard, Alex; Blank, Robert D.; Livingston, Janet; Raggio, Cathy L.; Rasmussen, Kristen; Pickart, Michael; Lorier, Rachel; Turner, Amy; Sund, Sarah; Sobrera, Nara; Neptune, Enid; Sweetser, David; Santiago-Cornier, Alberto; Broeckel, Ulrich.

In: American Journal of Medical Genetics, Part A, Vol. 167, No. 1, 01.01.2015, p. 95-102.

Research output: Contribution to journalArticle

Giampietro, PF, Armstrong, L, Stoddard, A, Blank, RD, Livingston, J, Raggio, CL, Rasmussen, K, Pickart, M, Lorier, R, Turner, A, Sund, S, Sobrera, N, Neptune, E, Sweetser, D, Santiago-Cornier, A & Broeckel, U 2015, 'Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes', American Journal of Medical Genetics, Part A, vol. 167, no. 1, pp. 95-102. https://doi.org/10.1002/ajmg.a.36799
Giampietro, Philip F. ; Armstrong, Linlea ; Stoddard, Alex ; Blank, Robert D. ; Livingston, Janet ; Raggio, Cathy L. ; Rasmussen, Kristen ; Pickart, Michael ; Lorier, Rachel ; Turner, Amy ; Sund, Sarah ; Sobrera, Nara ; Neptune, Enid ; Sweetser, David ; Santiago-Cornier, Alberto ; Broeckel, Ulrich. / Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes. In: American Journal of Medical Genetics, Part A. 2015 ; Vol. 167, No. 1. pp. 95-102.
@article{664e6afa6aa644c09ffe7049d651cca6,
title = "Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes",
abstract = "We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5{\%} of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.",
keywords = "Autosomal dominant, Klippel-Feil, Treacher Collins syndrome",
author = "Giampietro, {Philip F.} and Linlea Armstrong and Alex Stoddard and Blank, {Robert D.} and Janet Livingston and Raggio, {Cathy L.} and Kristen Rasmussen and Michael Pickart and Rachel Lorier and Amy Turner and Sarah Sund and Nara Sobrera and Enid Neptune and David Sweetser and Alberto Santiago-Cornier and Ulrich Broeckel",
year = "2015",
month = "1",
day = "1",
doi = "10.1002/ajmg.a.36799",
language = "English (US)",
volume = "167",
pages = "95--102",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes

AU - Giampietro, Philip F.

AU - Armstrong, Linlea

AU - Stoddard, Alex

AU - Blank, Robert D.

AU - Livingston, Janet

AU - Raggio, Cathy L.

AU - Rasmussen, Kristen

AU - Pickart, Michael

AU - Lorier, Rachel

AU - Turner, Amy

AU - Sund, Sarah

AU - Sobrera, Nara

AU - Neptune, Enid

AU - Sweetser, David

AU - Santiago-Cornier, Alberto

AU - Broeckel, Ulrich

PY - 2015/1/1

Y1 - 2015/1/1

N2 - We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.

AB - We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.

KW - Autosomal dominant

KW - Klippel-Feil

KW - Treacher Collins syndrome

UR - http://www.scopus.com/inward/record.url?scp=84919632833&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919632833&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.36799

DO - 10.1002/ajmg.a.36799

M3 - Article

C2 - 25348728

AN - SCOPUS:84919632833

VL - 167

SP - 95

EP - 102

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 1

ER -