Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomaliesCitation formats

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Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies. / Genomics England Research Consortium.

In: Genetics in medicine : official journal of the American College of Medical Genetics, 09.07.2021.

Research output: Contribution to journalArticlepeer-review

Harvard

Genomics England Research Consortium 2021, 'Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies', Genetics in medicine : official journal of the American College of Medical Genetics. https://doi.org/10.1038/s41436-021-01260-4

APA

Genomics England Research Consortium (2021). Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies. Genetics in medicine : official journal of the American College of Medical Genetics. https://doi.org/10.1038/s41436-021-01260-4

Vancouver

Genomics England Research Consortium. Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies. Genetics in medicine : official journal of the American College of Medical Genetics. 2021 Jul 9. https://doi.org/10.1038/s41436-021-01260-4

Author

Genomics England Research Consortium. / Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies. In: Genetics in medicine : official journal of the American College of Medical Genetics. 2021.

Bibtex

@article{113caac4877e46ad902552a8fc83b68f,
title = "Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies",
abstract = "PURPOSE: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition.METHODS: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable.RESULTS: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4.CONCLUSION: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.",
author = "{Genomics England Research Consortium} and Maria Iqbal and Reza Maroofian and B{\"u}{\c s}ranur {\c C}avdarlı and Florence Riccardi and Siddharth Banka and Bubshait, {Dalal K} and Jozef Hertecant and Baig, {Shahid Mahmood} and David Dyment and Stephanie Efthymiou and Uzma Abdullah and Makhdoom, {Ehtisham Ul Haq} and Zafar Ali and {Scherf de Almeida}, Tobias and Florence Molinari and C{\'e}cile Mignon-Ravix and Brigitte Chabrol and Jayne Antony and Lesley Ades and Pagnamenta, {Alistair T} and Adam Jackson and Sofia Douzgou and Christian Beetz and Vasiliki Karageorgou and Barbara Vona and Aboulfazl Rad and Baig, {Jamshaid Mahmood} and Tipu Sultan and Alvi, {Javeria Raza} and Shazia Maqbool and Fatima Rahman and Toosi, {Mehran Beiraghi} and Farah Ashrafzadeh and Shima Imannezhad and Yasra Sarwar and Muhammad Jameel and Noegel, {Angelika A} and Birgit Budde and Janine Altm{\"u}ller and Susanne Motameny and Wolfgang H{\"o}hne and Henry Houlden and Peter N{\"u}rnberg and Bernd Wollnik and Laurent Villard and Alkuraya, {Fowzan Sami} and Matthew Osmond and Hussain, {Muhammad Sajid} and G{\"o}khan Yigit",
note = "{\textcopyright} 2021. The Author(s). Funding Information: We are grateful to all family members that participated in this study. This work was supported by the Higher Education Commission (HEC) of Pakistan to M.I. and E.U.H. M.; the Center for Molecular Medicine Cologne (CMMC) (Projects 38-RP and C12; 2635/8029/01 and 2635/8326/01) to P.N. and M.S.H.; the Koeln Fortune Program (Faculty of Medicine, University of Cologne; 381/2020) to M.S.H.; Intramural Funding from the Fortune Program (Faculty of Medicine, University of T{\"u}bingen; 2545-1-0) and the Ministry of Science, Research and Art Baden-W{\"u}rttemberg to B.V.; the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) under Germany{\textquoteright}s Excellence Strategy–EXC 2067/1-390729940 to B.W.; the Medical Research Council (MRC) (MR/S01165X/1, MR/S005021/1, G0601943), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA) to H.H.; sequencing of family 3 was performed under the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, and Children{\textquoteright}s Hospital of Eastern Ontario Foundation. Three of the authors of this publication are members of the European Reference Network for Intellectual Disability, Telehealth and Congenital Anomalies (ERN-ITHACA; Project ID No 739543) (F.Riccardi; S.Banka; S.Douzgou). Family 5 was collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) (WT093205 MA and WT104033AIA) funding and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Genomic data for family 8 was generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. A.J. is supported by Solve-RD. The Solve-RD project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement number 779257. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = jul,
day = "9",
doi = "10.1038/s41436-021-01260-4",
language = "English",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams & Wilkins",

}

RIS

TY - JOUR

T1 - Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies

AU - Genomics England Research Consortium

AU - Iqbal, Maria

AU - Maroofian, Reza

AU - Çavdarlı, Büşranur

AU - Riccardi, Florence

AU - Banka, Siddharth

AU - Bubshait, Dalal K

AU - Hertecant, Jozef

AU - Baig, Shahid Mahmood

AU - Dyment, David

AU - Efthymiou, Stephanie

AU - Abdullah, Uzma

AU - Makhdoom, Ehtisham Ul Haq

AU - Ali, Zafar

AU - Scherf de Almeida, Tobias

AU - Molinari, Florence

AU - Mignon-Ravix, Cécile

AU - Chabrol, Brigitte

AU - Antony, Jayne

AU - Ades, Lesley

AU - Pagnamenta, Alistair T

AU - Jackson, Adam

AU - Douzgou, Sofia

AU - Beetz, Christian

AU - Karageorgou, Vasiliki

AU - Vona, Barbara

AU - Rad, Aboulfazl

AU - Baig, Jamshaid Mahmood

AU - Sultan, Tipu

AU - Alvi, Javeria Raza

AU - Maqbool, Shazia

AU - Rahman, Fatima

AU - Toosi, Mehran Beiraghi

AU - Ashrafzadeh, Farah

AU - Imannezhad, Shima

AU - Sarwar, Yasra

AU - Jameel, Muhammad

AU - Noegel, Angelika A

AU - Budde, Birgit

AU - Altmüller, Janine

AU - Motameny, Susanne

AU - Höhne, Wolfgang

AU - Houlden, Henry

AU - Nürnberg, Peter

AU - Wollnik, Bernd

AU - Villard, Laurent

AU - Alkuraya, Fowzan Sami

AU - Osmond, Matthew

AU - Hussain, Muhammad Sajid

AU - Yigit, Gökhan

N1 - © 2021. The Author(s). Funding Information: We are grateful to all family members that participated in this study. This work was supported by the Higher Education Commission (HEC) of Pakistan to M.I. and E.U.H. M.; the Center for Molecular Medicine Cologne (CMMC) (Projects 38-RP and C12; 2635/8029/01 and 2635/8326/01) to P.N. and M.S.H.; the Koeln Fortune Program (Faculty of Medicine, University of Cologne; 381/2020) to M.S.H.; Intramural Funding from the Fortune Program (Faculty of Medicine, University of Tübingen; 2545-1-0) and the Ministry of Science, Research and Art Baden-Württemberg to B.V.; the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) under Germany’s Excellence Strategy–EXC 2067/1-390729940 to B.W.; the Medical Research Council (MRC) (MR/S01165X/1, MR/S005021/1, G0601943), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA) to H.H.; sequencing of family 3 was performed under the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, and Children’s Hospital of Eastern Ontario Foundation. Three of the authors of this publication are members of the European Reference Network for Intellectual Disability, Telehealth and Congenital Anomalies (ERN-ITHACA; Project ID No 739543) (F.Riccardi; S.Banka; S.Douzgou). Family 5 was collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) (WT093205 MA and WT104033AIA) funding and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Genomic data for family 8 was generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. A.J. is supported by Solve-RD. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Publisher Copyright: © 2021, The Author(s).

PY - 2021/7/9

Y1 - 2021/7/9

N2 - PURPOSE: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition.METHODS: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable.RESULTS: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4.CONCLUSION: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.

AB - PURPOSE: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition.METHODS: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable.RESULTS: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4.CONCLUSION: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.

U2 - 10.1038/s41436-021-01260-4

DO - 10.1038/s41436-021-01260-4

M3 - Article

C2 - 34244665

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

ER -