Prader-Willi Syndrome and Chromosome 15q11.2 BP1-BP2 Region: A Review

Abstract

Prader-Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes (NIPA1, NIPA2, CYFIP1, TUBGCP5) from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion. NIPA1 and NIPA2 genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The CYFIP1 gene encodes a protein associated with fragile X syndrome. The TUBGCP5 gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside-Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions.

Keywords: 15q11.2 BP1-BP2 deletion; PWS molecular genetic classes; Prader–Willi syndrome (PWS); Type II deletions; clinical findings; typical 15q11-q13 Type I.

Figure 1

(A) A profile view from a 16-year-old female with Prader–Willi syndrome (PWS) showing central obesity as a major feature of this disorder. (B) A self-injury site noted in a separate patient with PWS, an abnormal clinical finding often seen in PWS.

Figure 2

Chromosome 15q11-q13 region with gene and transcript symbols in blue and the location causing Prader–Willi syndrome (PWS) imprinted with paternal expression. Angelman syndrome (AS) and maternal expression is in red, including the causative AS gene (UBE3A). The non-imprinted genes are green. The three 15q11-q13 breakpoints (BP1, BP2 and BP3) are the sites for the three chromosome 15q deletions; the larger Type I at BP1 and BP3, smaller Type II at BP2 and BP3 and the 15q11.2 BP1-BP2 deletion alone designated as Burnside–Butler syndrome. IC designates the imprinting center that controls the activity of the imprinted genes in the region and dependent on the parent of origin. The 15q11.2 BP1-BP2 region is enlarged and illustrated at the top.

Figure 3

Frontal views of a mother and child with the 15q11.2 BP1-BP2 deletion (Burnside–Butler) syndrome.