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Diagnostic Exome Sequencing Identifies Two Novel IQSEC2 Mutations Associated with X-Linked Intellectual Disability with Seizures: Implications for Genetic Counseling and Clinical Diagnosis

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Journal of Genetic Counseling


Intellectual disability is a heterogeneous disorder with a wide phenotypic spectrum. Over 1,700 OMIM genes have been associated with this condition, many of which reside on the X-chromosome. The IQSEC2 gene is located on chromosome Xp11.22 and is known to play a significant role in the maintenance and homeostasis of the brain. Mutations in IQSEC2 have been historically associated with nonsyndromic X-linked intellectual disability. Case reports of affected probands show phenotypic overlap with conditions associated with pathogenic MECP2, FOXG1, CDKL5, and MEF2C gene mutations. Affected individuals, however, have also been identified as presenting with additional clinical features including seizures, autistic-behavior, psychiatric problems, and delayed language skills. To our knowledge, only 5 deleterious mutations and 2 intragenic duplications have been previously reported in IQSEC2. Here we report two novel IQSEC2 de novo truncating mutations identified through diagnostic exome sequencing in two severely affected unrelated male probands manifesting developmental delay, seizures, hypotonia, plagiocephaly, and abnormal MRI findings. Overall, diagnostic exome sequencing established a molecular diagnosis for two patients in whom traditional testing methods were uninformative while expanding on the mutational and phenotypic spectrum. In addition, our data suggests that IQSEC2 may be more common than previously appreciated, accounting for approximately 9 % (2/22) of positive findings among patients with seizures referred for diagnostic exome sequencing. Further, these data supports recently published data suggesting that IQSEC2 plays a more significant role in the development of X-linked intellectual disability with seizures than previously anticipated.

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We are grateful to the patients and their families for their participation.


This manuscript is submitted solely to this journal and was not published elsewhere. We have submitted a similar version of the manuscript’s abstract to the American Society of Human Genetics conference for poster presentation at the 2013 educational conference.

Consent Process and IRB Exemption Status for Case Reports

Based on the definition of research as outlined in The Federal Policy for the Protection of Human Subjects (45 CFR 46.102(d)), case reports of 3 or fewer patients do not meet the criteria for human-subject research and do not need IRB review and approval since these reports do not involve the formulation of a research hypothesis, implementation of research investigation, or systematic and prospective data collection. Therefore, it was determined that our 2 cases reported here met the criteria for exemption from IRB review and approval under these Federal regulations. Proper documented informed consent meeting Federal criteria was obtained verbally and in writing from all patients and their family members involved in this case report, in compliance with the requirements outlined in The Federal Policy for the Protection of Human Subjects (Protection of Human Subjects 2009). Additionally, proper written informed consent for the use of photographs was also obtained by the clinicians involved in this case report.

Disclosures of Conflicts-of-Interest

Authors S. K. Gandomi, K.D. Farwell Gonzalez, M. Parra, L. Shahmirzadi, W. Zeng, and S. Tang are full-time salaried employees of Ambry Genetics, which is a commercial-based sequencing laboratory. These authors have no financial or commercial conflicts-of-interest to disclose beyond their basic employment with the laboratory. No outside funding was obtained nor was any other internal or external resource received for the analysis or publication process of this report. All laboratory data for this report was collected retrospectively after diagnostic testing had been completed for clinical purposes, and therefore the creation of this report does not additionally contribute to any relational or financial conflicts-of-interest with the referring providers.

Authors J. Mancuso, P. Pichurin, R. Temme, S. Dugan are associated with Mayo Clinic and Children’s Hospital & Clinics of Minnesota and do not have any conflicts-of-interest to disclose and are separate, independent entities from Ambry Genetics. They do not have any financial relationship with Ambry Genetics beyond a standard clinical nature.

Ambry Genetics has full control of the laboratory data associated with the DES testing process, and agrees to allow the journal to review the data if requested.

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Correspondence to Stephanie K. Gandomi.

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Gandomi, S.K., Farwell Gonzalez, K.D., Parra, M. et al. Diagnostic Exome Sequencing Identifies Two Novel IQSEC2 Mutations Associated with X-Linked Intellectual Disability with Seizures: Implications for Genetic Counseling and Clinical Diagnosis. J Genet Counsel 23, 289–298 (2014).

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