Dataset Information

Copy Number Variation Analysis of 5p Deletion Provides Accurate Prenatal Diagnosis and Reveals Candidate Pathogenic Genes

ABSTRACT:

Objective

5p deletion syndrome, that characterized by cat-like cry and peculiar timbre of voice, is believed to be one of the most common pathogenic copy number variations (CNVs). Variable critical regions on 5p involving a variety of genes contribute to the phenotypic heterogeneity without specific correlation. The objective of this study was to examine the genotype–phenotype correlation of 5p deletion syndrome, and to redefine 5p deletion syndrome relevant regions. In addition, we demonstrate the potential use of whole genome sequencing (WGS) to identify chromosomal breakpoints in prenatal diagnosis.

Methods

Three families with women undergoing prenatal diagnosis and two children were recruited. Karyotyping, CNV-seq, fluorescence in situ hybridization, WGS, and Sanger sequencing were performed to identify the chromosomal disorder.

Results

We reported three families and two children with CNVs of 5p deletion or combined 6p duplication. Five different sizes of 5p deletion were detected and their pathogenicity was determined, including 5p15.33-p15.31 [1–7,700,000, family1-variant of uncertain significance (VUS)], 5p15.33 (1–3,220,000, family 2-VUS), 5p15.33-p15.31 (1–7,040,000, family 3-VUS), 5p15.33-p15.31 (1–8,740,000, child 1-pathogenic) and 5p15.31-p15.1 (8,520,001–18,080,000, child 2-pathogenic). One duplication at 6p25.3-p24.3 (1–10,420,000) was detected and determined as likely pathogenic. The chromosomal breakpoints in family 3 were successfully identified by WGS.

Conclusion

Some critical genes that were supposed to be causative of the symptoms were identified. Relevant region in 5p deletion syndrome was redefined, and the chr5:7,700,000–8,740,000 region was supposed to be responsible for the cat-like cry. The great potential of WGS in detecting chromosomal translocations was demonstrated. Our findings may pave the way for further research on the prevention, diagnosis, and treatment of related diseases.

SUBMITTER: Chu G

PROVIDER: S-EPMC9329539 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe 8p23.1 duplication syndrome and copy number variation of the 8p23.1 defensin gene cluster are cytogenetically indistinguishable but distinct at the molecular level. To our knowledge, the 8p23.1 duplication syndrome has been described at prenatal diagnosis only once and we report our experience with four further apparent duplications ascertained at prenatal diagnosis.MethodsAdditional material at band 8p23.1 was detected using conventional G-banded cytogenetics in each case. Multiplex Ligation-dependent Probe Amplification (MLPA) or Fluorescence In Situ Hybridisation (FISH) were used depending on whether only DNA (Cases 1 and 4) or cytogenetic preparations (Cases 2 and 3) were available from the laboratory of origin. The extent of the duplication in Case 1 was retrospectively determined using array Comparative Genomic Hybridisation (array CGH).ResultsThree cases of 8p23.1 duplication syndrome were found (Cases 1 to 3). Two were de novo and continued to term and the third, a paternally transmitted duplication, was terminated because of a previous child with psychomotor delay and 8p23.1 duplication syndrome. Case 1 was ascertained with a hypoplastic left heart but the ventricular septal and interventricular defects, in Cases 2 and 3 respectively, were found after ascertainment for advanced maternal age. By contrast, case 4 was a maternally transmitted copy number variation of the defensin cluster with normal outcome.ConclusionsOur data underline the need to differentiate 8p23.1 duplications from copy number variation of the defensin cluster using FISH, MLPA or array CGH. Cardiac defects were ascertained by ultrasound in only one of the three duplication 8p23.1 pregnancies but were visible in two of the three at 21 to 22 weeks gestation. Our results provide further evidence that both deletion and duplication of the GATA4 transcription factor can give rise to a variety of conotruncal heart defects with variable penetrance and expressivity.