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Maternal interchromosomal insertional translocation leading to 1q43-q44 deletion and duplication in two siblings.

ABSTRACT: Background:1q43-q44 deletion syndrome is a well-defined chromosomal disorder which is characterized by moderate to severe mental retardation, and variable but characteristic facial features determined by the size of the segment and the number of genes involved. However, patients with 1q43-q44 duplication with a clinical phenotype comparable to that of 1q43-q44 deletion are rarely reported. Moreover, pure 1q43-q44 deletions and duplications derived from balanced insertional translocation within the same family with precisely identified breakpoints have not been reported. Case presentation:The proband is a 6-year-old girl with profound developmental delay, mental retardation, microcephaly, epilepsy, agenesis of the corpus callosum and hearing impairment. Her younger brother is a 3-month-old boy with macrocephaly and mild developmental delay in gross motor functions. G-banding analysis of the subjects at the 400-band level did not reveal any subtle structural changes in their karyotypes. However, single-nucleotide polymorphism (SNP) array analysis showed a deletion and a duplication of approximately 6.0 Mb at 1q43-q44 in the proband and her younger brother, respectively. The Levicare analysis pipeline of whole-genome sequencing (WGS) further demonstrated that a segment of 1q43-q44 was inserted at 14q23.1 in the unaffected mother, which indicated that the mother was a carrier of a 46,XX,ins(14;1)(q23.1;q43q44) insertional translocation. Moreover, Sanger sequencing was used to assist the mapping of the breakpoints and the final validation of those breakpoints. The breakpoint on chromosome 1 disrupted the EFCAB2 gene in the first intron, and the breakpoint on chromosome 14 disrupted the PRKCH gene within the 12th intron. In addition, fluorescence in situ hybridization (FISH) further confirmed that the unaffected older sister of the proband carried the same karyotype as the mother. Conclusion:Here, we describe a rare family exhibiting pure 1q43-q44 deletion and duplication in two siblings caused by a maternal balanced insertional translocation. Our study demonstrates that WGS with a carefully designed analysis pipeline is a powerful tool for identifying cryptic genomic balanced translocations and mapping the breakpoints at the nucleotide level and could be an effective method for explaining the relationship between karyotype and phenotype.

SUBMITTER: Luo A

PROVIDER: S-EPMC5883343 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Maternal interchromosomal insertional translocation leading to 1q43-q44 deletion and duplication in two siblings.

Luo Aixiang A Cheng Dehua D Yuan Shimin S Li Haiyu H Du Juan J Zhang Yang Y Yang Chuanchun C Lin Ge G Zhang Wenyong W Tan Yue-Qiu YQ

Molecular cytogenetics 20180404

<h4>Background</h4>1q43-q44 deletion syndrome is a well-defined chromosomal disorder which is characterized by moderate to severe mental retardation, and variable but characteristic facial features determined by the size of the segment and the number of genes involved. However, patients with 1q43-q44 duplication with a clinical phenotype comparable to that of 1q43-q44 deletion are rarely reported. Moreover, pure 1q43-q44 deletions and duplications derived from balanced insertional translocation ...[more]

PMID: 29636822

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Project description:BACKGROUND:Intellectual disability (ID) is a complex condition that can impact multiple domains of development. The genetic contribution to ID's etiology is significant, with more than 100 implicated genes and loci currently identified. The majority of such variants are rare and de novo genetic mutations. METHODS:We have applied whole-genome microarray to identify large, rare, clinically relevant copy number variants (CNVs). We have applied well-established algorithms for variants call. Quantitative polymerase chain reaction (qPCR) was applied to validate the variants using three technical replicates for each family member. To assess whether the copy number variation was due to balanced translocation or mosaicism, we further conducted droplet digital PCR (ddPCR) on the whole family. We have, as well, applied "critical-exon" mapping, human developmental brain transcriptome, and a database of known associated neurodevelopmental disorder variants to identify candidate genes. RESULTS:Here we present two siblings who are both impacted by a large terminal duplication and a deletion. Whole-genome microarray revealed an 18.82 megabase (MB) duplication at terminal locus (7q34-q36.3) of chromosome 7 and a 3.90 MB deletion impacting the terminal locus (15q26.3) of chromosome 15. qPCR and ddPCR experiments confirmed the de novo origin of the variants and the co-occurrence of these two de novo events among the siblings, but their absence in both parents, implicates an unbalanced translocation that could have mal-segregated among the siblings or a possible germline mosaicism. These terminal events impact IGF1R, CNTNAP2, and DPP6, shown to be strongly associated with neurodevelopmental disorders. Detailed clinical examination of the siblings revealed the presence of both shared and distinct phenotypic features. CONCLUSIONS:This study identified two large rare terminal de novo events impacting two siblings. Further phenotypic investigation highlights that even in the presence of identical large high penetrant variants, spectrum of clinical features can be different between the siblings.

Dataset Information

Maternal interchromosomal insertional translocation leading to 1q43-q44 deletion and duplication in two siblings.

Publications

Maternal interchromosomal insertional translocation leading to 1q43-q44 deletion and duplication in two siblings.

Similar Datasets

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