Identification and analysis of deletion breakpoints in four Mohr-Tranebjærg syndrome (MTS) patients

Abstract

Mohr-Tranebjærg syndrome is an X-linked syndrome characterized by sensorineural hearing impairment in childhood, followed by progressive neurodegeneration leading to a broad phenotypic spectrum. Genetically MTS is caused by pathogenic variants in the TIMM8A gene, including gene deletions and larger contiguous gene deletions. Some of the latter involve the neighboring gene BTK, resulting in agammaglobulinemia. By next‐generation mate‐pair sequencing we have mapped the chromosomal deletion breakpoints of one MTS case and three XLA-MTS cases and used breakpoint-spanning PCR to fine map the breakpoints by Sanger sequencing. Two of the XLA-MTS cases presented with large deletions (63.5 and 27.2 kb), and the junctional regions were characterized by long stretches of microhomology, indicating that the events have emerged through homologous recombination. Conversely, the MTS case exhibited a small 2 bp region of microhomology, and the regions were not characterized by extensive microhomology. The third XLA-MTS case had a more complex breakpoint, including a 59 bp inverted insertion, thus at least four breakpoints were involved in this event. In conclusion, mate-pair library generation combined with next-generation sequencing is an efficient method for breakpoint identification, also in regions characterized by repetitive elements.

Co-Occurring X-Linked Agammaglobulinemia and X-Linked Chronic Granulomatous Disease: Two Isolated Pathogenic Variants in One Patient

“…The X-chromosome, which is approximately three times larger than the Y chromosome, contains 900 genes, including CYBB (located on Xp21.1) and BTK (mapped to the Xq21.3-Xq22 region) [ 17 ]. Both CYBB and BTK have been associated with large deletions leading to co-existing genetic diagnoses with other genes: Lhomme et al describe this rare association of large deletions containing additional genes in eight XCGD patients with McLeod phenotype (neuroacanthosis) and Duchene muscular dystrophy (DMD) or Retinitis Pigmentosa (RP) [ 18 , 19 ], and in XLA, large deletions have included a neighboring gene to BTK ( TIMM8A ) causing Mohr–Tranebjaerg syndrome, an X-linked sensorineural hearing loss impairment in childhood with progression to neurodegeneration [ 20 ]. Such examples are important to identify in order to understand differences in the genetics of our patient from those previously reported, as the CYBB and BTK variants in the patient we described are neither large deletions nor impacting each other, as in the case of neighboring genes.…”