Iqbal, Maria, Maroofian, Reza, Cavdarli, Busranur, Riccardi, Florence ORCID: 0000-0002-7223-2172, Field, Michael, Banka, Siddharth ORCID: 0000-0002-8527-2210, Bubshait, Dalal K., Li, Yun, Hertecant, Jozef, Baig, Shahid Mahmood, Dyment, David, Efthymiou, Stephanie ORCID: 0000-0003-4900-9877, Abdullah, Uzma ORCID: 0000-0002-7168-8266, Makhdoom, Ehtisham Ul Haq, Ali, Zafar ORCID: 0000-0002-2389-3337, de Almeida, Tobias Scherf, Molinari, Florence ORCID: 0000-0001-5111-7215, Mignon-Ravix, Cecile, Chabrol, Brigitte, Antony, Jayne, Ades, Lesley, Pagnamenta, Alistair T., Jackson, Adam, Douzgou, Sofia, Beetz, Christian, Karageorgou, Vasiliki, Vona, Barbara ORCID: 0000-0002-6719-3447, Rad, Aboulfazl, Baig, Jamshaid Mahmood, Sultan, Tipu, Alvi, Javeria Raza, Maqbool, Shazia, Rahman, Fatima, Toosi, Mehran Beiraghi, Ashrafzadeh, Farah, Imannezhad, Shima, Karimiani, Ehsan Ghayoor, Sarwar, Yasra, Khan, Sheraz ORCID: 0000-0003-3207-4074, Jameel, Muhammad, Noegel, Angelika A., Budde, Birgit ORCID: 0000-0001-9385-4168, Altmueller, Janine, Motameny, Susanne, Hoehne, Wolfgang, Houlden, Henry, Nuernberg, Peter, Wollnik, Bernd ORCID: 0000-0003-2589-0364, Villard, Laurent ORCID: 0000-0001-6657-5008, Alkuraya, Fowzan Sami, Osmond, Matthew, Hussain, Muhammad Sajid ORCID: 0000-0002-1353-8809 and Yigit, Gokhan ORCID: 0000-0003-2777-0198 (2021). Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies. Genet. Med., 23 (11). S. 2138 - 2150. LONDON: SPRINGERNATURE. ISSN 1530-0366

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Iqbal, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maroofian, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cavdarli, BusranurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riccardi, FlorenceUNSPECIFIEDorcid.org/0000-0002-7223-2172UNSPECIFIED
Field, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Banka, SiddharthUNSPECIFIEDorcid.org/0000-0002-8527-2210UNSPECIFIED
Bubshait, Dalal K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hertecant, JozefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dyment, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Efthymiou, StephanieUNSPECIFIEDorcid.org/0000-0003-4900-9877UNSPECIFIED
Abdullah, UzmaUNSPECIFIEDorcid.org/0000-0002-7168-8266UNSPECIFIED
Makhdoom, Ehtisham Ul HaqUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, ZafarUNSPECIFIEDorcid.org/0000-0002-2389-3337UNSPECIFIED
de Almeida, Tobias ScherfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Molinari, FlorenceUNSPECIFIEDorcid.org/0000-0001-5111-7215UNSPECIFIED
Mignon-Ravix, CecileUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chabrol, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antony, JayneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ades, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pagnamenta, Alistair T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jackson, AdamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Douzgou, SofiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beetz, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karageorgou, VasilikiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vona, BarbaraUNSPECIFIEDorcid.org/0000-0002-6719-3447UNSPECIFIED
Rad, AboulfazlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Jamshaid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sultan, TipuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alvi, Javeria RazaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maqbool, ShaziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahman, FatimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toosi, Mehran BeiraghiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ashrafzadeh, FarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imannezhad, ShimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karimiani, Ehsan GhayoorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarwar, YasraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, SherazUNSPECIFIEDorcid.org/0000-0003-3207-4074UNSPECIFIED
Jameel, MuhammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noegel, Angelika A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, BirgitUNSPECIFIEDorcid.org/0000-0001-9385-4168UNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houlden, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDorcid.org/0000-0003-2589-0364UNSPECIFIED
Villard, LaurentUNSPECIFIEDorcid.org/0000-0001-6657-5008UNSPECIFIED
Alkuraya, Fowzan SamiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osmond, MatthewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad SajidUNSPECIFIEDorcid.org/0000-0002-1353-8809UNSPECIFIED
Yigit, GokhanUNSPECIFIEDorcid.org/0000-0003-2777-0198UNSPECIFIED
URN: urn:nbn:de:hbz:38-607171
DOI: 10.1038/s41436-021-01260-4
Journal or Publication Title: Genet. Med.
Volume: 23
Number: 11
Page Range: S. 2138 - 2150
Date: 2021
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTOCADHERIN-ALPHA FAMILY; GAMMA-PROTOCADHERINS; HOMOPHILIC INTERACTION; ORGANIZATION; MODULATION; DIVERSITY; APOPTOSIS; SURVIVAL; ADHESION; DOMAINMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60717

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