Three siblings with Prader–Willi syndrome caused by imprinting center microdeletions and review

Abstract

Prader-Willi syndrome (PWS) is a complex genetic imprinting disorder characterized by childhood obesity, short stature, hypogonadism/hypogenitalism, hypotonia, cognitive impairment, and behavioral problems. Usually PWS occurs sporadically due to the loss of paternally expressed genes on chromosome 15 with the majority of individuals having the 15q11-q13 region deleted. Examples of familial PWS have been reported but rarely. To date 13 families have been reported with more than one child with PWS and without a 15q11-q13 deletion secondary to a chromosome 15 translocation, inversion, or uniparental maternal disomy 15. Ten of those 13 families were shown to carry microdeletions in the PWS imprinting center. The microdeletions were found to be of paternal origin in nine of the ten cases in which family studies were carried out. Using a variety of techniques, the microdeletions were identified in regions within the complex SNRPN gene locus encompassing the PWS imprinting center. Here, we report the clinical and genetic findings in three adult siblings with PWS caused by a microdeletion in the chromosome 15 imprinting center inherited from an unaffected father that controls the activity of genes in the 15q11-q13 region and summarize the 13 reported cases in the literature.

Analysis of the Prader–Willi syndrome imprinting center using droplet digital PCR and next‐generation whole‐exome sequencing

“…The ddPCR data generated from the siblings' father were very similar to the microdeletion status seen in the two siblings (e.g., 0.9 and 1.0 vs. 0.8 in the father) using the IC1 probe (see Table ). These results were confirmed by MS‐MLPA analysis in a previous study (Hartin et al, ). The ddPCR results in the siblings' mother using the three IC probes showed a nondeletion status with ddPCR data and approximately twice the CN of the probes seen in other family members (e.g., 1.5 vs. 0.7 in the father using probe IC2; 1.6 vs. 0.8 in the father using probe IC1 and 1.4 vs. 0.6 in the father using probe SNRPN exon 1) (see Table ).…”

“… Two of the three PWS siblings had microdeletions larger than 100 kb in size (reported in Hartin et al, ). …”

“…Genetic characterization of three siblings (PWS7‐9) and both parents were reported in Hartin, Hossain, Weisensel, & Butler, . Of the three siblings, PWS7 was the only one to have Illumina and Affymetrix high‐resolution studies completed.…”

Established and emerging strategies to crack the genetic code of obesity

“…Cytogenetics continues to be applicable to many clinical and research settings. For example, it is frequently used to characterize genetic abnormalities in PWS and has propelled research on the role of non‐coding RNAs in this disorder .…”

Possibility of early diagnosis in a fetus affected by Prader‑Willi syndrome with maternal hetero‑UPD15: A lesson to be learned

“…As a complicated neurodevelopmental genetic disorder, PWS classically presents with severe hypotonia and feeding difficulties in the neonatal period, sometimes with concurrent anorexia and a sucking deficit (2). Challenged by the difficulties in early diagnosis, care and treatment, the majority of patients gain excessive weight at three or four years of age, and begin to exhibit signs of developmental delay and hypogonadism, eventually leading to severe early obesity, intellectual disability, cognitive impairment, genital hypoplasia and infertility (3,4). PWS is characterized by a sporadic occurrence, which does not discriminate among gender or race, with an estimated prevalence of 1 in 15,000–30,000 live births (5).…”