Abstract

Prader–Willi syndrome (PWS) is a complex genetic syndrome caused by the loss of function of genes in 15q11-q13 that are subject to regulation by genomic imprinting and expressed from the paternal allele only. The main clinical features of PWS patients are hypotonia during the neonatal and infantile stages, accompanied by delayed neuropsychomotor development, hyperphagia, obesity, hypogonadism, short stature, small hands and feet, mental disabilities, and behavioral problems. However, PWS has a clinical overlap with other disorders, especially those with other gene variations or chromosomal imbalances but sharing part of the similar clinical manifestations with PWS, which are sometimes referred to as Prader–Willi syndrome-like (PWS-like) disorders. Furthermore, it is worth mentioning that significant obesity as a consequence of hyperphagia in PWS usually develops between the ages of 1 and 6 years, which makes early diagnosis difficult. Thus, PWS is often not clinically recognized in infants and, on the other hand, may be wrongly suspected in obese and intellectually disabled patients. Therefore, an accurate investigation is necessary to differentiate classical PWS from PWS-like phenotypes, which is imperative for further treatment. For PWS, it is usually sporadic, and very rare family history and affected siblings have been described. Here, we report the clinical and molecular findings in a three-generation family with a novel 550-kb microdeletion affecting the chromosome 15 imprinting center (IC). Overall, the present study finds that the symptoms of our patient are somewhat different from those of typical PWS cases diagnosed and given treatment in our hospital. The familial occurrence and clinical features were challenging to our diagnostic strategy. The microdeletion included a region within the complex small nuclear ribonucleoprotein polypeptide protein N (SNRPN) gene locus encompassing the PWS IC and was identified by using a variety of techniques. Haplotype studies suggest that the IC microdeletion was vertically transmitted from an unaffected paternal grandmother to an unaffected father and then caused PWS in two sibling grandchildren when the IC microdeletion was inherited paternally. Based on the results of our study, preimplantation genetic diagnosis (PGD) was applied successfully to exclude imprinting deficiency in preimplantation embryos before transfer into the mother’s uterus. Our study may be especially instructive regarding accurate diagnosis, differential diagnosis, genetic counseling, and PGD for familial PWS patients.

Highlights

  • The Prader–Willi syndrome (PWS) is characterized by hypotonia and feeding problems in early infancy, as well as hypogonadism, small hands and feet, craniofacial signs, and hyperphagia leading to profound obesity

  • Whole-Exome Sequencing and Copy Number Variation Copy number variation analysis of the proband identified a 500-kb interstitial microdeletion of 15q11.2 with the first breakpoint located at 24,932,524 bp and the last breakpoint at 25,482,598 bp on the distal region

  • We extended the genetic analysis to the family members of the patient

Read more

Summary

Introduction

The Prader–Willi syndrome (PWS) is characterized by hypotonia and feeding problems in early infancy, as well as hypogonadism, small hands and feet, craniofacial signs, and hyperphagia leading to profound obesity. It is triggered by the loss of function of genes in 15q11-q13 that are regulated by genomic imprinting and expressed from the paternal allele only. To the best of our knowledge, familial transmission of the IC microdeletion or multiple affected siblings have been proven to be very rare, and only four familial PWS cases with IC microdeletion transmitted through three generations have been reported so far (Hartin et al, 2018). We aimed to share our case presentation and explore some useful methodology for detecting the silent transmission of PWS IC microdeletion through the female germline that may cause considerable difficulties in diagnostic testing and genetic counseling in affected families

Objectives
Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call