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Original Investigation |

Identification of an HMGB3 Frameshift Mutation in a Family With an X-linked Colobomatous Microphthalmia Syndrome Using Whole-Genome and X-Exome Sequencing

Alan F. Scott, PhD1; David W. Mohr, BA1; Laura M. Kasch, BS1; Jill A. Barton, MS1; Raquel Pittiglio, MS1; Roxann Ingersoll, MHS1; Brian Craig, MS1; Beth A. Marosy, MS1; Kimberly F. Doheny, PhD1; William C. Bromley, MD2; Thomas H. Roderick, PhD†2; Nicolas Chassaing, MD3; Patrick Calvas, MD3; Shreya S. Prabhu, MD4; Ethylin Wang Jabs, MD1,4
[+] Author Affiliations
1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
2The Jackson Laboratory, Center for Human Genetics, Bar Harbor, Maine
3CHU Toulouse, Service de Génétique Médicale, Hôpital Purpan, Université Paul-Sabatier Toulouse III, Toulouse, France
4Icahn School of Medicine at Mount Sinai, New York, New York
JAMA Ophthalmol. 2014;132(10):1215-1220. doi:10.1001/jamaophthalmol.2014.1731.
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Importance  Microphthalmias are rare disorders whose genetic bases are not fully understood. HMGB3 is a new candidate gene for X-linked forms of this disease.

Objective  To identify the causative gene in a pedigree with an X-linked colobomatous microphthalmos phenotype.

Design, Setting, and Participants  Whole-genome sequencing and chromosome X-exome–targeted sequencing were performed at the High Throughput Sequencing Laboratory of the Genetic Resources Core Facility at the Johns Hopkins University School of Medicine on the DNA of the male proband and informatically filtered to identify rare variants. Polymerase chain reaction and Sanger sequencing were used to confirm the variant in the proband and the carrier status of his mother. Thirteen unrelated male patients with a similar phenotype were also screened.

Main Outcomes and Measures  Whole-genome and X-exome sequencing to identify a frameshift variant in HMGB3.

Results  A 2–base pair frameshift insertion (c.477_478insTA, coding for p.Lys161Ilefs*54) in the HGMB3 gene was found in the proband and his carrier mother but not in the unrelated patients. The mutation, confirmed by 3 orthogonal methods, alters an evolutionarily conserved region of the HMGB3 protein from a negatively charged polyglutamic acid tract to a positively charged arginine-rich motif that is likely to interfere with normal protein function.

Conclusions and Relevance  In this family, microphthalmia, microcephaly, intellectual disability, and short stature are associated with a mutation on the X chromosome in the HMGB3 gene. HMGB3 should be considered when performing genetic studies of patients with similar phenotypes.

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Figure 1.
Original Pedigree Redrawn to Indicate the Proband and His Mother

No other family members were available at the time of this study. Squares indicate males; circles, females; filled symbols, affected individuals; arrowhead, sequenced proband; diamonds, sex undesignated; numbers within a symbol, numbers of males or females counted together; triangles, miscarriages. Adapted with permission of Elsevier from Goldberg and McKusick.3

Graphic Jump Location
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Figure 2.
Alignment of Sanger Sequence From the Proband Against the Human HMGB3 Reference cDNA NM_005342.2

Exon 4 was amplified by polymerase chain reaction and sequenced. The resulting sequence was in agreement with the insertion/deletion identified from the Illumina X-exome and Complete Genomics whole-genome sequences.

Graphic Jump Location
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Figure 3.
Conservation of HMGB3 Protein Sequences

The predicted frameshifted protein is highlighted in red. Species differences from human are italicized.

Graphic Jump Location

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