Phenotypic variability of a deletion and duplication 6q16.1 → q21 due to a paternal balanced ins(7;6)(p15;q16.1q21)

Abstract

Constitutional insertional translocations are rare findings in clinical cytogenetics. Here, we report on the unbalanced segregation of a balanced paternal insertional translocation ins(7;6)(p15;q16.1q21) to three children. Investigations by conventional karyotyping, FISH with locus-specific probes, microsatellite marker analysis, and SNP-array based copy number analysis revealed a direct orientation of the inserted segment, a size of 11.3 Mb, and breakpoints between rs4370337 and rs12660854 and rs12110990 and rs4946730 on 6q16.1 and 6q21, respectively, as well as within BAC clone RP11-182J2 on 7p15. A 17-year-old daughter inherited the der(6) chromosome and was affected by severe mental retardation, obesity, and minor anomalies. Two further children inherited the der(7) chromosome. A daughter shows an almost unremarkable phenotype and only minor features in neuropsychological testing at 19 years of age. Her 14-year-old half-brother demonstrates a mild delay in cognitive development most likely jointly caused by the chromosomal rearrangement and asphyxia during delivery. The patient with the deletion confirms the previously reported phenotype of severe mental retardation and obesity in patients with del(6)(q16.2), while both patients with partial trisomy for the same segment of chromosome 6 are further examples for a generally less severe phenotype associated with duplications than with deletions, and even for the recent insight that chromosomal aneusomies of several megabases may go without major clinical consequences.

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

“…Other observations support this hypothesis. 18,19 In our series, only two of nine deletions in patients, for whom parental-origin data were obtained, were located in the maternal chromosome, which is consistent with the ratio reported previously for interstitial deletions at any site. 44 In another study, de novo imbalances not mediated by low copy repeats were significantly more often of paternal than of maternal origin.…”

“…3, However, few of them underwent molecular characterisation of their genetic abnormalities, using either chromosomal microarray analysis, 3,13,[15][16][17][18]22,23,25 fluorescence in situ hybridisation (FISH) analysis with bacterial artificial chromosomes (BAC) clones 21 or STR analysis. 24 Two publications evaluated genotype-phenotype correlations at the 6q16 locus, but included only five and three patients, respectively.…”

Genotype–phenotype correlation in interstitial 6q deletions: a report of 12 new cases

“…A critical region for limb anomalies has been proposed within 6q21; individuals with deletions that encompass 6q21 have had split hand malformation, which is often unilateral and asymmetric including one individual with polydactyly of the opposing hand [2, [12][13][14][15]. Deletion of SIM1 at 6q16.3 has been proposed as the cause of a Prader-Willi (PW)-like phenotype in some individuals with interstitial 6q deletions [11,[16][17][18][19][20][21]. In contrast, there has been a single case report of an individual with a PW-like phenotype whose 6q22.2q23.1 deletion likely did not include SIM1, nor did it overlap with other deletions associated with this phenotype [22].…”

“…higher resolution techniques such as microarray-based comparative genomic hybridization (aCGH) [1][2][3][4][5][6][7][8][9][10][11].…”

Multiple Congenital Anomalies and Global Developmental Delay in a Patient with Interstitial 6q25.2q26 Deletion: A Diagnostic Odyssey

“…Spreiz et al [2010] described an individual with a balanced ins(7; 6)(p15;q16.1q21) resulting in deletion 6q16.1q21 in one of his daughters and duplication 6q16.1q21 in his 2 other children. The mechanism and the origin of the deletion seen in our patient are unknown.…”