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Chapter 11. Neurogenetics

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A 7-year-old boy presents for evaluation of developmental disability. Birth history was remarkable for decreased fetal movement and difficulty feeding due to poor suck in the neonatal period. Current examination reveals morbid obesity. Examination also demonstrates hypogonadism, short stature, and diffuse hypotonia. During the examination, the patient had numerous temper tantrums. Genetic evaluation of this patient will most likely reveal:

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(A) Paternal uniparental disomy of 15q11-q13

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(B) Paternal microdeletion at 15q11-q13

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(C) Trisomy of chromosome 15 with loss of maternal 15q

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(D) Balanced translocation of 15q11-q13 causing paternal uniparental disomy

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(E) Normal parent-specific methylation studies

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(B) The patient in the vignette has Prader–Willi syndrome. Clinically, he has the characteristic constellation of symptoms which includes behavioral problems, developmental/intellectual disability, diffuse hypotonia, hypogonadism, and hyperphagia. Interestingly, because of the overwhelming hypotonia present at birth, children with Prader–Willi syndrome are exceedingly thin and are often categorized as “failure to thrive."  It is not until later in life that children with Prader-Willi syndrome develop morbid obesity.

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Genetically, Prader-Willi and Angelman syndromes are categorized together, as they are both associated with abnormalities within the chromosome region 15q11-q13. However, the phenotypic differences seem to stem based on the parental origin of the genetic anomaly. Prader–Willi occurs due to paternal inheritance of a cytogenetic anomaly at 15q11-q13, whereas Angelman syndrome occurs when that abnormality is maternally inherited. Prader–Willi occurs most commonly due to paternal microdeletion at 15q11-q13. Additionally, absence of the paternal region of 15q11-q13 can occur due to maternal uniparental disomy of that region, as opposed to paternal uniparental disomy, choice A. Similarly, a balanced translocation of 15q11-q13 leading to maternal uniparental disomy would lead to Prader–Willi syndrome, but a translocation leading to a paternal uniparental disomy (choice D) would not. Likewise, although trisomy 15 with loss of the paternal chromosome 15 can cause Prader–Willi syndrome, a trisomy 15 with associated loss of the maternal chromosome 15 (answer choice B) does not, but would lead to Angelman syndrome. Parent-specific DNA methylation analysis is rarely normal (choice D) in Prader–Willi syndrome and will actually detect nearly all (>99%) of individuals with the syndrome. (Cassidy, 917–923; Cassidy and Driscoll, 3–13; Cassidy, Lai, et al, 701–708; Cassidy, Schwartz, et al, 10–26).

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Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997;34: 917–923.

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Cassidy SB, Driscoll DJ. Prader–Willi syndrome. Eur J Hum Genet. 2009;17:3–13.

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Cassidy SB, Lai LW, Erickson RP, et al. Trisomy 15 with loss of the paternal 15 as a cause of Prader–Willi syndrome due to maternal disomy. Am J Hum Genet. 1992; 51(4): 701–708.

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Cassidy SB, Schwartz S, Miller JL, Driscroll DJ. ...

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