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 journalArticlepeer-review

61 Scopus citations


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 languageEnglish (US)
Pages (from-to)545-552
Number of pages8
JournalGenetics in Medicine
Issue number3
StatePublished - 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.


  • autozygome
  • dwarfism
  • primary microcephaly

ASJC Scopus subject areas

  • Genetics(clinical)


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