The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3.

Abstract

BACKGROUND:

The mutations in UNC13D are responsible for familial hemophagocytic lymphohistiocytosis (FHL) type 3. A 253-kb inversion and two deep intronic mutations, c.118-308C > T and c.118-307G > A, in UNC13D were recently reported in European and Asian FHL3 patients. We sought to determine the prevalence of these three non-coding mutations in North American FHL patients and evaluate the significance of examining these new mutations in genetic testing.

PROCEDURE:

We performed DNA sequencing of UNC13D and targeted analysis of these three mutations in 1,709 North American patients with a suspected clinical diagnosis of hemophagocytic lymphohistiocytosis (HLH).

RESULTS:

The 253-kb inversion, intronic mutations c.118-308C > T and c.118-307G > A were found in 11, 15, and 4 patients, respectively, in which the genetic basis (bi-allelic mutations) explained 25 additional patients. Taken together with previously diagnosed FHL3 patients in our HLH patient registry, these three non-coding mutations were found in 31.6% (25/79) of the FHL3 patients. The 253-kb inversion, c.118-308C > T and c.118-307G > A accounted for 7.0%, 8.9%, and 1.3% of mutant alleles, respectively. Significantly, eight novel mutations in UNC13D are being reported in this study. To further evaluate the expression level of the newly reported intronic mutation c.118-307G > A, reverse transcription PCR and Western blot analysis revealed a significant reduction of both RNA and protein levels suggesting that the c.118-307G > A mutation affects transcription.

CONCLUSIONS:

These specified non-coding mutations were found in a significant number of North American patients and inclusion of them in mutation analysis will improve the molecular diagnosis of FHL3.

• Authors: Yaping Qian, Judith A Johnson, Jessica A Connor, C Alexander Valencia, Nathaniel Barasa, Jeffery Schubert, Ammar Husami, Diane Kissell, Ge Zhang, Matthew T Weirauch, Alexandra H Filipovich, Kejian Zhang
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 61 Issue 6 Pg. 1034-40 (Jun 2014) ISSN: 1545-5017 [Electronic] United States
• PMID: 24470399 (Publication Type: Journal Article)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Membrane Proteins
• UNC13D protein, human

Topics

• Adolescent
• Adult
• Black or African American (genetics)
• Arabs (genetics)
• Asian (genetics)
• Child
• Chromosome Inversion
• Consanguinity
• DNA Mutational Analysis
• Female
• Genetic Testing
• Hispanic or Latino (genetics)
• Humans
• Infant
• Infant, Newborn
• Introns (genetics)
• Lymphohistiocytosis, Hemophagocytic (ethnology, genetics)
• Male
• Membrane Proteins (chemistry, genetics, physiology)
• North America (epidemiology)
• Point Mutation
• Sequence Analysis, DNA
• White People (genetics)
• Young Adult