Sage Journals: Discover world-class research

Abstract

Objective

Herein, we report a case of a deceased newborn with prenatally detected hydrocephalus. Postnatal findings included abnormal brain imaging and electroencephalogram, optic nerve abnormalities, and elevated creatine kinase (CK). No underlying genetic etiology had been previously identified for the proband, despite testing with a congenital muscular dystrophy gene panel.

Methods

Diagnostic exome sequencing (DES) was performed on the proband-parents trio, and candidate alterations were confirmed using automated fluorescence dideoxy sequencing.

Results

Exome sequencing of the proband, mother and father identified a previously unreported apparently de novo heterozygous tubulin, beta-3 (TUBB3) c.523G>C (p.V175L) alteration in the proband.

Conclusion

Overall, DES established a likely molecular genetic diagnosis for a postmortem case after traditional testing methods were uninformative. The DES results allowed for reproductive options, such as preimplantation genetic diagnosis and/or prenatal diagnosis, to be available to the parents in future pregnancies.

Keywords

TUBB3 protein human exome clinical diagnostic sequencing postmortem diagnosis Walker–Warburg syndrome abnormal brain hydrocephalus

Get full access to this article

View all access options for this article.

References

Farwell

Shahmirzadi

El-Khechen

et al.

Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med 2015; 17(7): 578–586.

Craddock

St George

Freedman

et al.

Computational predictions of volatile anesthetic interactions with the microtubule cytoskeleton: implications for side effects of general anesthesia. PLoS One 2012; 7(6): e37251.

Kim

Chivian

Baker

. Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res 2004; 32(Web Server issue): W526–W531.

Camacho

Coulouris

Avagyan

et al.

BLAST+: architecture and applications. BMC Bioinformatics 2009; 10: 421.

Schymkowitz

Rousseau

Martins

Ferkinghoff-Borg

Stricher

Serrano

. Prediction of water and metal binding sites and their affinities by using the Fold-X force field. Proc Natl Acad Sci U S A 2005; 102(29): 10147–10152.

Abraham

Murtolad

Schulzb

et al.

GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015; 1–2: 6.

International HapMap

. The International HapMap Project. Nature 2003; 426(6968): 789–796.

Adzhubei

Schmidt

Peshkin

et al.

A method and server for predicting damaging missense mutations. Nat Methods 2010; 7(4): 248–249.

Kumar

Henikoff

. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009; 4(7): 1073–1081.

10.

Tischfield

Baris

et al.

Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 2010; 140(1): 74–87.

11.

Mignot

Pecqueur

Dorleans

et al.

Design and characterization of modular scaffolds for tubulin assembly. J Biol Chem 2012; 287(37): 31085–31094.

12.

Niwa

Takahashi

Hirokawa

. beta-Tubulin mutations that cause severe neuropathies disrupt axonal transport. EMBO J 2013; 32(10): 1352–1364.

13.

Tischfield

Cederquist

Gupta

Jr Engle

. Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations. Curr Opin Genet Dev 2011; 21(3): 286–294.

14.

Poirier

Saillour

Bahi-Buisson

et al.

Mutations in the neuronal ss-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects. Hum Mol Genet 2010; 19(22): 4462–4473.

15.

Fallet-Bianco

Laquerriere

Poirier

et al.

Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly. Acta Neuropathol Commun 2014; 2: 69.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.59 MB

Postmortem Diagnostic Exome Sequencing Identifies a De Novo TUBB3 Alteration in a Newborn With Prenatally Diagnosed Hydrocephalus and Suspected Walker–Warburg Syndrome

Abstract

Objective

Methods

Results

Conclusion

Keywords

Get full access to this article

References

Supplementary Material