Abstract
Disorders of cobalamin deficiency are a heterogeneous group of disorders with at least 19 autosomal recessive-associated genes. Familial samples of an infant who died due to presumed cobalamin deficiency were referred for clinical exome sequencing. The patient died before obtaining a blood sample or skin biopsy, autopsy was declined, and DNA yielded from the newborn screening blood spot was insufficient for diagnostic testing. Whole-exome sequencing of the mother, father, and unaffected sister and tailored bioinformatics analysis was applied to search for mutations in underlying disorders with recessive inheritance. This approach identified alterations within two genes, each of which was carried by one parent. The mother carried a missense alteration in the MTR gene (c.3518C>T; p.P1173L) which was absent in the father and the sister. The father carried a translational frameshift alteration in the LMBRD1 gene (c.1056delG; p.L352Lfs*18) which was absent in the mother and present in the heterozygous state in the sister. These mutations in the MTR (MIM# 156570) and LMBRD1 (MIM# 612625) genes have been described in patients with disorders of cobalamin metabolism complementation groups cblG and cblF, respectively. The child’s clinical presentation and biochemical results demonstrated overlap with both cblG and cblF. Sanger sequencing using DNA from the infant’s blood spot confirmed the inheritance of the two alterations in compound heterozygous form. We present the first example of exome sequencing leading to a diagnosis in the absence of the affected patient. Furthermore, the data support the possibility for potential digenic inheritance associated with cobalamin deficiency.
Competing interests: None declared
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We are grateful to the family of the patient for their participation.
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Synopsis
In this report, we simultaneously demonstrate the power of new molecular technologies to diagnose a deceased patient while uncovering the first potential example of digenic inheritance associated with cobalamin deficiency.
Conflict of Interest
Kelly Gonzalez, Xiang Li, Hsiao-Mei Lu, Hong Lu, Elizabeth Chao, and Wenqi Zeng are employed and receive a salary from Ambry Genetics. Exome sequencing is among the commercially available tests. Joan Pellegrino and Ryan Miller declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for which identifying information is included in this article.
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This article does not contain any studies with animal subjects performed by any of the authors.
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Kelly Gonzalez was involved in the study’s conception and design, analysis and interpretation of data, and drafting the article and is the guarantor for the manuscript. Xiang Li, Hsiao-Mei Lu, and Hong Lu were involved in analysis and interpretation of data and critical review and revision of drafts for important intellectual content. Joan Pellegrino and Ryan Miller were involved in drafting the article, analysis and interpretation of data, and critical review and revision of drafts for important intellectual content. Elizabeth Chao and Wenqi Zeng were involved in the study’s conception and design, analysis and interpretation of data, and critical review and revision of drafts for important intellectual content.
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ESP [Internet]: Exome variant server, NHLBI GO exome sequencing project (ESP), Seattle, WA. http://evs.gs.washington.edu/EVS/. Accessed Feb 2013.
OMIM [Internet]: Online Mendelian inheritance in man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD. World Wide Web. http://omim.org/. Accessed 2 June 2013.
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Farwell Gonzalez, K.D. et al. (2014). Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 15. JIMD Reports, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_294
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DOI: https://doi.org/10.1007/8904_2014_294
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