Dual molecular diagnosis contributes to atypical Prader–Willi phenotype in monozygotic twins

Abstract

We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed the apparently de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the splice site variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins showed that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.

Two unrelated individuals carrying rare mosaic deletions in TCF4 gene

“…The rarity of mosaicism for TCF4 deletions or mutations in PTHS patients adds a significant scientific and diagnostic value to any new findings of this type. A total of 11 individuals are currently found to carry various mosaic aberrations affecting TCF4 and exhibit various phenotypes (de Pontual et al, ; Essaoui et al, ; Giurgea et al, ; Jehee et al, ; Rossi et al, ; Stavropoulos et al, ). A list of all patients with phenotypic data is presented on Table .…”

22q and two: 22q11.2 deletion syndrome and coexisting conditions

“…Previous reports of clinicians investigating for a secondary diagnosis often occur when a disease with a well-known phenotype presents with atypical severity (Jehee et al, 2017). For example, while the individual features of esophageal atresia, optic nerve coloboma, and sensorineural hearing loss, can each be observed in 22q11.2DS, the combination of all three in a single patient triggered consideration of an alternative unifying diagnosis, in this case CHARGE syndrome.…”

Faculty Opinions recommendation of Insights into genetics, human biology and disease gleaned from family based genomic studies.

“…56,57,[105][106][107][108][109] Presenting phenotypes may be distinct or overlapping, and may obscure clinical ascertainment, and parental mosaicism can impact recurrence risk. 56,110 • Mutational burden and modifiers can modulate the phenotypic severity of the observed trait, and may explain intrafamilial phenotypic variability, as has been observed in peripheral neuropathy. 111 Similarly, an aggregation of rare variants has been shown to influence susceptibility to Parkinson disease, 112 and the age of onset of ALS.…”