Genomic and phenotypic delineation of congenital microcephaly

Ranad Shaheen; Sateesh Maddirevula; Nour Ewida; Saud Alsahli; Ghada M.H. Abdel-Salam; Maha S. Zaki; Saeed Al Tala; Amal Alhashem; Ameen Softah; Mohammed Al-Owain; Anas M. Alazami; Basma Abadel; Nitinkumar Patel; Tarfa Al-Sheddi; Rana Alomar; Eman Alobeid; Nofal Ibrahim; Mais Hashem; Firdous Abdulwahab; Muddathir Hamad; Brahim Tabarki; Ali H. Alwadei; Fahad Alhazzani; Fahad A. Bashiri; Amal Kentab; Serdar Şahintürk; Elliott Sherr; Brieana Fregeau; Samira Sogati; Saad Ali M. Alshahwan; Salwa Alkhalifi; Zainab Alhumaidi; Samia Temtamy; Mona Aglan; Ghada Otaify; Katta M. Girisha; Maha Tulbah; Mohammed Zain Seidahmed; Mustafa A. Salih; Mohamed Abouelhoda; Afaque A. Momin; Muna Al Saffar; Jennifer N. Partlow; Stefan T. Arold; Eissa Faqeih; Christopher Walsh; Fowzan S. Alkuraya

doi:10.1038/s41436-018-0140-3

Genomic and phenotypic delineation of congenital microcephaly

Ranad Shaheen, Sateesh Maddirevula, Nour Ewida, Saud Alsahli, Ghada M.H. Abdel-Salam, Maha S. Zaki, Saeed Al Tala, Amal Alhashem, Ameen Softah, Mohammed Al-Owain, Anas M. Alazami, Basma Abadel, Nitinkumar Patel, Tarfa Al-Sheddi, Rana Alomar, Eman Alobeid, Nofal Ibrahim, Mais Hashem, Firdous Abdulwahab, Muddathir HamadBrahim Tabarki, Ali H. Alwadei, Fahad Alhazzani, Fahad A. Bashiri, Amal Kentab, Serdar Şahintürk, Elliott Sherr, Brieana Fregeau, Samira Sogati, Saad Ali M. Alshahwan, Salwa Alkhalifi, Zainab Alhumaidi, Samia Temtamy, Mona Aglan, Ghada Otaify, Katta M. Girisha, Maha Tulbah, Mohammed Zain Seidahmed, Mustafa A. Salih, Mohamed Abouelhoda, Afaque A. Momin, Muna Al Saffar, Jennifer N. Partlow, Stefan T. Arold, Eissa Faqeih, Christopher Walsh, Fowzan S. Alkuraya^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly —as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference—is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2,YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

Original language	English (US)
Pages (from-to)	545-552
Number of pages	8
Journal	Genetics in Medicine
Volume	21
Issue number	3
DOIs	https://doi.org/10.1038/s41436-018-0140-3
State	Published - Mar 1 2019

Bibliographical note

Funding Information:
This work was supported by the King Salman Center for Disability Research (F.S.A.), King Abdulaziz City for Science and Technology (13-BIO1113-20, F.S.A.), and the Saudi Human Genome Program (F.S.A.). M.A.S. was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia through the research group project number RGP-VPP-301. The research by S.T.A. and A.A.M. reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST). C.A.W. was supported by the Manton Center for Orphan Disease Research and a grant from the National Institute of Neurological Disorders and Stroke (R01 NS035129) and is an Investigator of the Howard Hughes Medical Institute. We thank the study families for their enthusiastic participation and the Sequencing and Genotyping Core Facilities at King Faisal Specialist Hospital and Research Centre (KFSHRC) for their technical help.

Publisher Copyright:
© 2018, American College of Medical Genetics and Genomics.

Keywords

CNTRL
autozygome
dwarfism
primary microcephaly

ASJC Scopus subject areas

Genetics(clinical)

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10.1038/s41436-018-0140-3

Cite this

Shaheen, R., Maddirevula, S., Ewida, N., Alsahli, S., Abdel-Salam, G. M. H., Zaki, M. S., Tala, S. A., Alhashem, A., Softah, A., Al-Owain, M., Alazami, A. M., Abadel, B., Patel, N., Al-Sheddi, T., Alomar, R., Alobeid, E., Ibrahim, N., Hashem, M., Abdulwahab, F., ... Alkuraya, F. S. (2019). Genomic and phenotypic delineation of congenital microcephaly. Genetics in Medicine, 21(3), 545-552. https://doi.org/10.1038/s41436-018-0140-3

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title = "Genomic and phenotypic delineation of congenital microcephaly",

abstract = "Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly —as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference—is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2,YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.",

keywords = "CNTRL, autozygome, dwarfism, primary microcephaly",

author = "Ranad Shaheen and Sateesh Maddirevula and Nour Ewida and Saud Alsahli and Abdel-Salam, {Ghada M.H.} and Zaki, {Maha S.} and Tala, {Saeed Al} and Amal Alhashem and Ameen Softah and Mohammed Al-Owain and Alazami, {Anas M.} and Basma Abadel and Nitinkumar Patel and Tarfa Al-Sheddi and Rana Alomar and Eman Alobeid and Nofal Ibrahim and Mais Hashem and Firdous Abdulwahab and Muddathir Hamad and Brahim Tabarki and Alwadei, {Ali H.} and Fahad Alhazzani and Bashiri, {Fahad A.} and Amal Kentab and Serdar {\c S}ahint{\"u}rk and Elliott Sherr and Brieana Fregeau and Samira Sogati and Alshahwan, {Saad Ali M.} and Salwa Alkhalifi and Zainab Alhumaidi and Samia Temtamy and Mona Aglan and Ghada Otaify and Girisha, {Katta M.} and Maha Tulbah and Seidahmed, {Mohammed Zain} and Salih, {Mustafa A.} and Mohamed Abouelhoda and Momin, {Afaque A.} and Saffar, {Muna Al} and Partlow, {Jennifer N.} and Arold, {Stefan T.} and Eissa Faqeih and Christopher Walsh and Alkuraya, {Fowzan S.}",

note = "Funding Information: This work was supported by the King Salman Center for Disability Research (F.S.A.), King Abdulaziz City for Science and Technology (13-BIO1113-20, F.S.A.), and the Saudi Human Genome Program (F.S.A.). M.A.S. was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia through the research group project number RGP-VPP-301. The research by S.T.A. and A.A.M. reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST). C.A.W. was supported by the Manton Center for Orphan Disease Research and a grant from the National Institute of Neurological Disorders and Stroke (R01 NS035129) and is an Investigator of the Howard Hughes Medical Institute. We thank the study families for their enthusiastic participation and the Sequencing and Genotyping Core Facilities at King Faisal Specialist Hospital and Research Centre (KFSHRC) for their technical help. Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

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month = mar,

day = "1",

doi = "10.1038/s41436-018-0140-3",

language = "English (US)",

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Shaheen, R, Maddirevula, S, Ewida, N, Alsahli, S, Abdel-Salam, GMH, Zaki, MS, Tala, SA, Alhashem, A, Softah, A, Al-Owain, M, Alazami, AM, Abadel, B, Patel, N, Al-Sheddi, T, Alomar, R, Alobeid, E, Ibrahim, N, Hashem, M, Abdulwahab, F, Hamad, M, Tabarki, B, Alwadei, AH, Alhazzani, F, Bashiri, FA, Kentab, A, Şahintürk, S, Sherr, E, Fregeau, B, Sogati, S, Alshahwan, SAM, Alkhalifi, S, Alhumaidi, Z, Temtamy, S, Aglan, M, Otaify, G, Girisha, KM, Tulbah, M, Seidahmed, MZ, Salih, MA, Abouelhoda, M, Momin, AA, Saffar, MA, Partlow, JN, Arold, ST, Faqeih, E, Walsh, C & Alkuraya, FS 2019, 'Genomic and phenotypic delineation of congenital microcephaly', Genetics in Medicine, vol. 21, no. 3, pp. 545-552. https://doi.org/10.1038/s41436-018-0140-3

TY - JOUR

T1 - Genomic and phenotypic delineation of congenital microcephaly

AU - Shaheen, Ranad

AU - Maddirevula, Sateesh

AU - Ewida, Nour

AU - Alsahli, Saud

AU - Abdel-Salam, Ghada M.H.

AU - Zaki, Maha S.

AU - Tala, Saeed Al

AU - Alhashem, Amal

AU - Softah, Ameen

AU - Al-Owain, Mohammed

AU - Alazami, Anas M.

AU - Abadel, Basma

AU - Patel, Nitinkumar

AU - Al-Sheddi, Tarfa

AU - Alomar, Rana

AU - Alobeid, Eman

AU - Ibrahim, Nofal

AU - Hashem, Mais

AU - Abdulwahab, Firdous

AU - Hamad, Muddathir

AU - Tabarki, Brahim

AU - Alwadei, Ali H.

AU - Alhazzani, Fahad

AU - Bashiri, Fahad A.

AU - Kentab, Amal

AU - Şahintürk, Serdar

AU - Sherr, Elliott

AU - Fregeau, Brieana

AU - Sogati, Samira

AU - Alshahwan, Saad Ali M.

AU - Alkhalifi, Salwa

AU - Alhumaidi, Zainab

AU - Temtamy, Samia

AU - Aglan, Mona

AU - Otaify, Ghada

AU - Girisha, Katta M.

AU - Tulbah, Maha

AU - Seidahmed, Mohammed Zain

AU - Salih, Mustafa A.

AU - Abouelhoda, Mohamed

AU - Momin, Afaque A.

AU - Saffar, Muna Al

AU - Partlow, Jennifer N.

AU - Arold, Stefan T.

AU - Faqeih, Eissa

AU - Walsh, Christopher

AU - Alkuraya, Fowzan S.

N1 - Funding Information: This work was supported by the King Salman Center for Disability Research (F.S.A.), King Abdulaziz City for Science and Technology (13-BIO1113-20, F.S.A.), and the Saudi Human Genome Program (F.S.A.). M.A.S. was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia through the research group project number RGP-VPP-301. The research by S.T.A. and A.A.M. reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST). C.A.W. was supported by the Manton Center for Orphan Disease Research and a grant from the National Institute of Neurological Disorders and Stroke (R01 NS035129) and is an Investigator of the Howard Hughes Medical Institute. We thank the study families for their enthusiastic participation and the Sequencing and Genotyping Core Facilities at King Faisal Specialist Hospital and Research Centre (KFSHRC) for their technical help. Publisher Copyright: © 2018, American College of Medical Genetics and Genomics.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly —as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference—is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2,YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

AB - Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly —as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference—is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2,YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

KW - CNTRL

KW - autozygome

KW - dwarfism

KW - primary microcephaly

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U2 - 10.1038/s41436-018-0140-3

DO - 10.1038/s41436-018-0140-3

M3 - Article

C2 - 30214071

AN - SCOPUS:85053661261

VL - 21

SP - 545

EP - 552

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 3

ER -

Genomic and phenotypic delineation of congenital microcephaly

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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