Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes.

Tiia Maria Luukkonen,Lars Paulin,Mana M Mehrjouy,Anna-Kaisa Anttonen,Päivi Lahermo,Niels Tommerup,Pekka Ellonen,Aarno Palotie,Minna Pöyhönen,Teppo Varilo

doi:10.1002/mgg3.346

Abstract

BackgroundThe risk of serious congenital anomaly for de novo balanced translocations is estimated to be at least 6%. We identified two apparently independent families with a balanced t(1;12)(q43;q21.1) as an outcome of a “Systematic Survey of Balanced Chromosomal Rearrangements in Finns.” In the first family, carriers (n = 6) manifest with learning problems in childhood, and later with unexplained neurological symptoms (chronic headache, balance problems, tremor, fatigue) and cerebral infarctions in their 50s. In the second family, two carriers suffer from tetralogy of Fallot, one from transient ischemic attack and one from migraine. The translocation cosegregates with these vascular phenotypes and neurological symptoms.Methods and ResultsWe narrowed down the breakpoint regions using mate pair sequencing. We observed conserved haplotypes around the breakpoints, pointing out that this translocation has arisen only once. The chromosome 1 breakpoint truncates a CHRM3 processed transcript, and is flanked by the 5′ end of CHRM3 and the 3′ end of RYR2. TRHDE,KCNC2, and ATXN7L3B flank the chromosome 12 breakpoint.ConclusionsThis study demonstrates a balanced t(1;12)(q43;q21.1) with conserved haplotypes on the derived chromosomes. The translocation seems to result in vascular phenotype, with or without neurological symptoms, in at least two families. We suggest that the translocation influences the positional expression of CHRM3,RYR2,TRHDE,KCNC2, and/or ATXN7L3B.

Highlights

Reciprocal balanced translocations are prevalent chromosomal aberrations with the incidence of c. 1:600 births
The translocation breakpoints mapped outside the putative protein-coding genes, pointing to malfunction caused by a position effect
Dysfunction may be induced via truncation of the CHRM3 processed transcript with a potential role in the regulation of protein coding CHRM3 expression, or alternatively via position effect triggered by disruption of a relevant regulatory element

Summary

| INTRODUCTION

Reciprocal balanced translocations are prevalent chromosomal aberrations with the incidence of c. 1:600 births. In t(8;22), the chromosome 8 palindromic ATrich repeat is flanked by two highly homologous Alu repeats that are in an inverted orientation with respect to one another These Alu elements may contribute to the translocation formation. The underlying pathogenetic mechanisms may be versatile, such as dosagesensitive break (single functional copy is insufficient for normal gene function), gene fusion (chimeric gene), position effect (dysregulation of gene expression through dislocation and disruption of noncoding elements such as RNA genes or conserved nongenic sequences; Dermitzakis, Reymond, & Antonarakis, 2005; Mattick, 2005), or unmasking of recessive variants (normal homologous chromosome becomes unmasked). The families suffer from vascular phenotypes including cerebral infarction and TOF

| MATERIALS AND METHODS

| DISCUSSION