Thirteen-day-old girl with hypotonia, born to parents who achieved the pregnancy using in-vitro fertilization (IVF). No other significant family history was available. The provider wanted to evaluate for a diagnosis of Prader-Willi syndrome (PWS) or Angelman syndrome (AS) and, if positive, desired to clarify the disease mechanism.
The correct answer is ...
The correct answer is: maternal heterodisomy for chromosome 15, <1% risk.
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy/early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.
Consensus clinical diagnostic criteria are accurate, but the mainstay of diagnosis is DNA methylation testing to detect abnormal imprinting patterns within the Prader-Willi critical region (PWCR) on chromosome 15; this testing determines whether the region is maternally inherited only (i.e., the paternally contributed region is absent) and has a sensitivity of at least 99%. DNA methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially in those who have atypical findings or are too young to manifest sufficient features to make the diagnosis on clinical grounds.
The MS-MLPA result for this patient shows absence of a deletion (unmethylated reaction); however, the digested reaction shows two copies of a methylated allele at maternally imprinted sites compared to a normal control. This result is consistent with a diagnosis of Prader-Willi syndrome.
To clarify disease mechanism, microsatellite markers are analyzed and compared between the parents and proband to evaluate for uniparental disomy. The results shows that the proband has inherited both copies of chromosome 15 from the mother (UPD15), and since non-identical alleles are present, this is consistent with heterodisomy.
Below is the recurrence risks for different mechanisms for Prader-Willi syndrome and Angelman syndrome.
Vishnu Vardhan Serla, M.D.
Fellow, Molecular Genetic Pathology
Nicole Lynn Hoppman, Ph.D.
Consultant, Laboratory Genetics and Genomics
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science