Clinical and Cytogenetic Impact of Maternal Balanced Double Translocation: A Familial Case of 15q11.2 Microduplication and Microdeletion Syndromes with Genetic Counselling Implications

Abstract

Background: Balanced chromosomal translocations occur in approximately 0.16 to 0.20% of live births. While most carriers are phenotypically normal, they are at risk of generating unbalanced gametes during meiosis, leading to genetic anomalies such as aneuploidies, deletions, duplications, and gene disruptions. These anomalies can result in spontaneous abortions or congenital anomalies, including neurodevelopmental disorders. Complex chromosomal rearrangements (CCRs) involving more than two chromosomes are rare but further increase the probability of producing unbalanced gametes. Neurodevelopmental disorders such as Angelman syndrome (AS) and duplication 15q11q13 syndrome (Dup15q) are associated with such chromosomal abnormalities.

Methods: This study describes a family with a de novo maternal balanced double translocation involving chromosomes 13, 19, and 15, resulting in two offspring with unbalanced chromosomal abnormalities. Cytogenetic evaluations were performed using GTG banding, fluorescence in situ hybridization (FISH), and low-pass whole-genome sequencing (LP-WGS). Methylation analysis was conducted using methylation-sensitive high-resolution melting (MS-HRM) to diagnose Angelman syndrome.

Results: The cytogenetic and molecular analyses identified an 8.9 Mb duplication in 15q11.2q13.3 in one child, and an 8.9 Mb deletion in the same region in the second child. Both abnormalities affected critical neurodevelopmental genes, such as SNRPN. FISH and MS-HRM confirmed the chromosomal imbalances and the diagnosis of Angelman syndrome in the second child. The maternal balanced translocation was found to be cryptic, contributing to the complex inheritance pattern.

Conclusion: This case highlights the importance of using multiple genetic platforms to uncover complex chromosomal rearrangements and their impact on neurodevelopmental disorders. The findings underscore the need for thorough genetic counseling, especially in families with such rare chromosomal alterations, to manage reproductive outcomes and neurodevelopmental risks.

Keywords: FISH; LP-WGS; double balanced translocation; genetic couseling.

Figure 1

Duplication and deletion of 8.9 Mb on 15q11.2q13.3 identified by LP-WGS. (A). Proband duplication characterizing 15q11q13 microduplication syndrome. (B) Proband’s sister deletion characterizing Angelman syndrome.

Figure 2

Methylation pattern of proband’s sister and proband, analyzed by MS-HRM. Amplifications plot related to normal (A), and Angelman syndrome (B). Normalized graphs (C,D) show initial fluorescence, where all products are double-stranded and bound to the maximum amount of dye. Normal patients present fluorescence drops corresponding to both paternal and maternal alleles (B). As the temperature rose, PCR products dissociated, releasing the dye and decreasing the fluorescent signal. The temperature differences between paternal and maternal alleles are attributed to the CpG binding chemistry. Methylated cytosines are nonreactive to bisulfite conversion while nonmethylated cytosines convert to uracil. CpG-rich regions require higher dissociation temperatures. The melting temperature detected for methylated maternal allele was 84.07 °C, and 79.5 °C for the nonmethylated paternal allele. Derivative graphs (E,F) illustrate the melting peak of each allele. The normal patient in derivative graphs (E) presents two peaks corresponding to the unmethylated (79.5 °C) and methylated (84.07 °C) alleles. The absence of maternal allele confirms Angelman syndrome (D,F). The different colors indicate experimental triplicates.

Figure 3

(A) Proband GTG analysis—Karyotype: 46,XX. (B) The FISH technique using Prader–Willi/Angelman region probe (SNRPN) demonstrating three red signals corresponding to 15q11.2 region in the proband. The arrow indicates the third red signal, confirming triplicate of the 15q11.2 region. (C) Proband´s sister analysis by GTG banding—Karyotype: 46,XX, t(13;19)(q22;p13.1). (D) The FISH analysis using Prader–Willi/Angelman region probe (SNRPN) demonstrating deletion of 15q11.2 region in proband’s sister.

Figure 4

(A) Mother’s karyotype by GTG banding—46,XX, t(13;19)(q22;p13.1) (B) Partial mother’s karyotype demonstrating translocation t(13;19) with breakpoints (arrows) (C) Mother’s FISH analysis using Prader–Willi/Angelman region probe (SNRPN) and chromosome 13 centromeric probe (D13Z1) showing a balanced translocation between the other homologue of chromosome 13 with one of chromosomes 15 (.ish t(13;15)(q12?;q12?) identified two green signals (D13Z1 and 15qter) at the same chromosome (derivative chromosome 13), a normal chromosome 15 (both signals red and green), and a derivative chromosome 15 showing only the red signal (15q11.2). The chromosome marked only with centromeric probe (D13Z1) is the derivative of t(13;19).

Figure 5

Three-generation pedigree. Shaded symbols denote affected individuals (III-4 = case 1 and III-5 = case 2), and stripe-patterned symbols indicate carriers of balanced translocations. Individuals I-2, I-3, II-3, II-6, and III-2 have a normal karyotype and/or FISH findings, with III-2 clinically diagnosed with Marfan syndrome and a variant of uncertain significance at seq[GRCh38] 15q13.3(31739865_32239864)x3, which is likely benign. The proband is marked with an arrow.