Molecular characterization of a patient with central nervous system dysmyelination and cryptic unbalanced translocation between chromosomes 4q and 18q

Abstract

We report on a 12-year-old boy who presented with delayed development and CNS dysmyelination. Genetic studies showed a normal 46,XY karyotype by routine cytogenetic analysis, and 46,XY.ish del(18)(q23)(D18Z1+, MBP-) by FISH using a locus-specific probe for the MBP gene (18q23). Though the patient appeared to have normal chromosome 18s by repeated high resolution banding analysis, his clinical features were suggestive of a deletion of 18q. These included hearing loss secondary to stenosis of the external auditory canals, abnormal facial features, and foot deformities. FISH studies with genomic probes from 18q22.3 to 18qter confirmed a cryptic deletion which encompassed the MBP gene. In an attempt to further characterize the deletion, whole genome screening was conducted using array based comparative genomic hybridization (array CGH) analysis. The array CGH data not only confirmed a cryptic deletion in the 18q22.3 to 18qter region of approximately 7 Mb, it also showed a previously undetected 3.7 Mb gain of 4q material. FISH studies demonstrated that the gained 4q material was translocated distal to the 18qter deletion breakpoint. The 18q deletion contains, in addition to MBP, other known genes including CYB5, ZNF236, GALR1, and NFATC1, while the gained 4q material includes the genes FACL1 and 2, KLKB1, F11 and MTNR1A. The use of these combined methodologies has resulted in the first reported case in which array CGH has been used to characterize a congenital chromosomal abnormality, highlighting the need for innovative molecular cytogenetic techniques in the diagnosis of patients with idiopathic neurological abnormalities.

Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations

“…The 3-kb LTR is an HERV-H transposable element. This element has been implicated in the formation of a de novo der(18)t(4;18)(q35.1;q22.3), complementary to the der(4)t(4;18)(q35.1;q22.3) identified here (Gunn et al 2003;Moncla et al 2004;Horbinski et al 2008;Hermetz et al 2012). In addition, in case 7, the breakpoint junction could not be sequenced, but the breakpoint region on both chromosomes harbors an intact 6-kb L1PA4 element, suggesting that NAHR occurred within.…”

Elucidation of a cryptic interstitial 7q31.3 deletion in a patient with a language disorder and mild mental retardation by array‐CGH

“…Using this technology, cases of unexplained MR can be investigated molecularly by performing a genome-wide scan of DNA imbalance [see Albertson and Pinkel, 2003 for review]. Gunn et al [2003] have recently demonstrated the use of array-CGH to reveal both cryptic gain and loss in a patient with a normal G-banded karyotype but with features suggestive of a chromosome abnormality. Therefore, to investigate the possibility of submicroscopic deletions or duplications at the breakpoints of the complex rearrangement in our patient, we used array-CGH to screen the whole genome of this patient at a resolution of 3 Mb.…”

Array-based comparative genomic hybridization: clinical contexts for targeted and whole-genome designs

“…Numerous studies have already emphasized the value of this approach. [31][32][33][34] The versatility of high-density oligonucleotide arrays is a function of in situ probe synthesis chemistry, the digital workflow that controls that synthesis, and creative feature and array formats. Users can generate customized arrays quickly for two possible clinical uses.…”