PraderWilli Syndrome (PWS [MIM 176270]) is a rare neurogenetic disorder mapping to the chromosome 15q11-q13 domain, which results from the genetic and epigenetic function deficiency of genomic imprinting of paternal alleles. It is characterized by neonatal hypotonia with following childhood obesity, hyperphagia, developmental delay and short stature, hypogonadism, cognitive impairment, and behavioral problems. PWS is generally sporadic that occurs in about 1 in 10 000 to 30 000 live births. The majority of individuals have the paternal deletion of proximal 15q, secondary to a chromosome 15 reciprocal translocation, inversion, uniparental maternal disomy 15, or imprinting defects. Familial inheritance of PWS has been reported but shows a rare familial simultaneous occurrence. We describe here the first reported familial cases in China of demonstrative findings of Prader-Willi syndrome and carry out family studies to analyze the different underlying cytogenetics mechanisms. In the first case, two affected sibs present the characteristic features with severe neonatal hypotony, hyporeflexia, little cry at birth and hypogonadism seen in PWS. They both harbour a paternally transmitted 417 kilobase pairs (kbp) [array15q11.2(24,963,375-25,380,656)x1] deletion in 15q11.2-q13 of the PWS imprinting region. The submicrodeletion, verified by single nucleotide polymorphism (SNP) array and methylation-specific MLPA (MS-MLPA), passes through the paternal line from the patients' father and paternal grandmother, both of whom carry a maternally derived deletion with clinically normal phenotypes. In the second case, there are two affected sibs fulfilling diagnostic criteria for typical PWS as well as one suspected cousin with milder cognitive impairment. The karyotype analysis of the patients and their mother showed the seemingly cytogenetic abnormality-45,XX,rob(15;15)(q10;q10) due to a translocation involving maternal chromosome 15 and hence effective maternal uniparental disomy for the PWS region. We provide the genetic findings of the probands' pedigrees in the aspects of clinical evaluations and conclude molecular cytogenetic mechanism analysis of Prader-Willi Syndrome, so as to a better prenatal diagnosis and corresponding genetic counseling in such families, especially when estimating the recurrence risks in families.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology