Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly

Irfan Ullah; Naseebullah Kakar; Isabelle Schrauwen; Shabir Hussain; Imen Chakchouk; Khurram Liaqat; Anushree Acharya; Naveed Wasif; Regie Lyn P. Santos-Cortez; Saadullah Khan; Abdul Aziz; Kwanghyuk Lee; Julien Couthouis; Denise Horn; Bjørt K. Kragesteen; Malte Spielmann; Holger Thiele; Deborah A. Nickerson; Michael J. Bamshad; Aaron D. Gitler; Jamil Ahmad; Muhammad Ansar; Guntram Borck; Wasim Ahmad; Suzanne M. Leal

doi:10.1007/s00439-019-02000-0

Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly

Irfan Ullah, Naseebullah Kakar, Isabelle Schrauwen, Shabir Hussain, Imen Chakchouk, Khurram Liaqat, Anushree Acharya, Naveed Wasif, Regie Lyn P. Santos-Cortez, Saadullah Khan, Abdul Aziz, Kwanghyuk Lee, Julien Couthouis, Denise Horn, Bjørt K. Kragesteen, Malte Spielmann, Holger Thiele, Deborah A. Nickerson, Michael J. Bamshad, Aaron D. GitlerJamil Ahmad, Muhammad Ansar, Guntram Borck, Wasim Ahmad, Suzanne M. Leal^*

^*Korrespondierende/r Autor/-in für diese Arbeit

20 Zitate (Scopus)

Abstract

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.

Originalsprache	Englisch
Zeitschrift	Human Genetics
Jahrgang	138
Ausgabenummer	6
Seiten (von - bis)	593-600
Seitenumfang	8
ISSN	0340-6717
DOIs	https://doi.org/10.1007/s00439-019-02000-0
Publikationsstatus	Veröffentlicht - 01.06.2019

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Acknowledgements The authors would like to thank the family members who participated in this study. This work was supported by funds from the Higher Education Commission (HEC), Islamabad, Pakistan (to WA). A Georg Forster fellowship was provided by the Alexander von Humboldt Foundation (to NW). Genotyping and exome sequencing for family BD204 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant UM1 HG006493 (to DAN, MJB, and SML) and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Web Resources: ANNOVAR, http:// annovar.openbioinformatics.org/. Burrows-Wheeler Aligner (BWA), http://bio-bwa.sourceforge.net/. Combined Annotation Dependent Depletion (CADD), http://cadd.gs.washington.edu/. Gene Expression Ommibus (GEO), https://www.ncbi.nlm.nih.gov/geo/. Genome Aggregation Database (gnomAD), http://gnomad.broadinstitute.org/. Genome Analysis Toolkit (GATK), https://software.broadinstitute.org/ gatk/. ENCODE project, https://www.encodeproject.org/. Homozygosi-tyMapper, http://www.homozygositymapper.org/. International Mouse Phenotyping Consortium (IMPC), http://www.mousephenotype.org. Varbank pipeline v.2.3, https://varbank.ccg.uni-koeln.de/.

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10.1007/s00439-019-02000-0

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Ullah, I., Kakar, N., Schrauwen, I., Hussain, S., Chakchouk, I., Liaqat, K., Acharya, A., Wasif, N., Santos-Cortez, R. L. P., Khan, S., Aziz, A., Lee, K., Couthouis, J., Horn, D., Kragesteen, B. K., Spielmann, M., Thiele, H., Nickerson, D. A., Bamshad, M. J., ... Leal, S. M. (2019). Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly. Human Genetics, 138(6), 593-600. https://doi.org/10.1007/s00439-019-02000-0

@article{292f7f649b6a4438a9ee46d6a5dafaf5,

title = "Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly",

abstract = "Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.",

author = "Irfan Ullah and Naseebullah Kakar and Isabelle Schrauwen and Shabir Hussain and Imen Chakchouk and Khurram Liaqat and Anushree Acharya and Naveed Wasif and Santos-Cortez, \{Regie Lyn P.\} and Saadullah Khan and Abdul Aziz and Kwanghyuk Lee and Julien Couthouis and Denise Horn and Kragesteen, \{Bj{\o}rt K.\} and Malte Spielmann and Holger Thiele and Nickerson, \{Deborah A.\} and Bamshad, \{Michael J.\} and Gitler, \{Aaron D.\} and Jamil Ahmad and Muhammad Ansar and Guntram Borck and Wasim Ahmad and Leal, \{Suzanne M.\}",

note = "Funding Information: Acknowledgements The authors would like to thank the family members who participated in this study. This work was supported by funds from the Higher Education Commission (HEC), Islamabad, Pakistan (to WA). A Georg Forster fellowship was provided by the Alexander von Humboldt Foundation (to NW). Genotyping and exome sequencing for family BD204 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant UM1 HG006493 (to DAN, MJB, and SML) and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Web Resources: ANNOVAR, http:// annovar.openbioinformatics.org/. Burrows-Wheeler Aligner (BWA), http://bio-bwa.sourceforge.net/. Combined Annotation Dependent Depletion (CADD), http://cadd.gs.washington.edu/. Gene Expression Ommibus (GEO), https://www.ncbi.nlm.nih.gov/geo/. Genome Aggregation Database (gnomAD), http://gnomad.broadinstitute.org/. Genome Analysis Toolkit (GATK), https://software.broadinstitute.org/ gatk/. ENCODE project, https://www.encodeproject.org/. Homozygosi-tyMapper, http://www.homozygositymapper.org/. International Mouse Phenotyping Consortium (IMPC), http://www.mousephenotype.org. Varbank pipeline v.2.3, https://varbank.ccg.uni-koeln.de/. Publisher Copyright: {\textcopyright} 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = jun,

day = "1",

doi = "10.1007/s00439-019-02000-0",

language = "English",

volume = "138",

pages = "593--600",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Oxford University Press",

number = "6",

}

Ullah, I, Kakar, N, Schrauwen, I, Hussain, S, Chakchouk, I, Liaqat, K, Acharya, A, Wasif, N, Santos-Cortez, RLP, Khan, S, Aziz, A, Lee, K, Couthouis, J, Horn, D, Kragesteen, BK, Spielmann, M, Thiele, H, Nickerson, DA, Bamshad, MJ, Gitler, AD, Ahmad, J, Ansar, M, Borck, G, Ahmad, W & Leal, SM 2019, 'Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly', Human Genetics, Jg. 138, Nr. 6, S. 593-600. https://doi.org/10.1007/s00439-019-02000-0

TY - JOUR

T1 - Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly

AU - Ullah, Irfan

AU - Kakar, Naseebullah

AU - Schrauwen, Isabelle

AU - Hussain, Shabir

AU - Chakchouk, Imen

AU - Liaqat, Khurram

AU - Acharya, Anushree

AU - Wasif, Naveed

AU - Santos-Cortez, Regie Lyn P.

AU - Khan, Saadullah

AU - Aziz, Abdul

AU - Lee, Kwanghyuk

AU - Couthouis, Julien

AU - Horn, Denise

AU - Kragesteen, Bjørt K.

AU - Spielmann, Malte

AU - Thiele, Holger

AU - Nickerson, Deborah A.

AU - Bamshad, Michael J.

AU - Gitler, Aaron D.

AU - Ahmad, Jamil

AU - Ansar, Muhammad

AU - Borck, Guntram

AU - Ahmad, Wasim

AU - Leal, Suzanne M.

N1 - Funding Information: Acknowledgements The authors would like to thank the family members who participated in this study. This work was supported by funds from the Higher Education Commission (HEC), Islamabad, Pakistan (to WA). A Georg Forster fellowship was provided by the Alexander von Humboldt Foundation (to NW). Genotyping and exome sequencing for family BD204 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant UM1 HG006493 (to DAN, MJB, and SML) and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Web Resources: ANNOVAR, http:// annovar.openbioinformatics.org/. Burrows-Wheeler Aligner (BWA), http://bio-bwa.sourceforge.net/. Combined Annotation Dependent Depletion (CADD), http://cadd.gs.washington.edu/. Gene Expression Ommibus (GEO), https://www.ncbi.nlm.nih.gov/geo/. Genome Aggregation Database (gnomAD), http://gnomad.broadinstitute.org/. Genome Analysis Toolkit (GATK), https://software.broadinstitute.org/ gatk/. ENCODE project, https://www.encodeproject.org/. Homozygosi-tyMapper, http://www.homozygositymapper.org/. International Mouse Phenotyping Consortium (IMPC), http://www.mousephenotype.org. Varbank pipeline v.2.3, https://varbank.ccg.uni-koeln.de/. Publisher Copyright: © 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.

AB - Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.

UR - https://www.scopus.com/pages/publications/85064498777

U2 - 10.1007/s00439-019-02000-0

DO - 10.1007/s00439-019-02000-0

M3 - Journal articles

C2 - 30982135

AN - SCOPUS:85064498777

SN - 0340-6717

VL - 138

SP - 593

EP - 600

JO - Human Genetics

JF - Human Genetics

IS - 6

ER -

Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly

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