General overview of the 15q11.2 region

Deletions and duplications of the 15q11.2 region (on chromosome 15) are frequent rearrangements. Prevalence is 1 over 250. Rearrangements happen between breakpoints (BP) BP1 and BP2 and extend over a distance of 250 kilobases. This segment contains four genes : GCP5, CYFIP1, NIPA1 and NIPA2, for which the exact functions are still misunderstood.


Microdeletion (BP1 & BP2)

Clinical description

A 15q11.2 microdeletion has incomplete penetrance and variable expression. This means that a carrier of this genetic change does not necessarily present manifestations and if so, those could vary between people. Some studies have suggested that supplemental factors are required to develop an intellectual disability or a psychiatric disorder. This explains the huge clinical variability between carriers of the microdeletion.

Associated malformations

  • Developmental delay
  • The majority of children who carry a 15q11.2 microdeletion presents a developmental delay and a speech delay. Especially, they can present dyslexia [Doornbos et al 2009; Burnside et al 2011; von der Lippe et al 2011]. They can also present dyscalculia (persistent and specific trouble of mathematical domain learning).

  • Neurological troubles
  • Carriers of a microdeletion often have cerebral abnormalities visible on MRI or EEG. They can also present epilepsy [de Korvel et al 2010; Mullen et al 2013], which is probably associated to the NIPA2 gene (Xie et al, 2014).

  • Behavioral and psychiatric troubles
  • In a general way, 55% of carriers would present a psychiatric or behavioural trouble. This includes attention deficit disorder, autism spectrum disorder, obsessive compulsive disorder, self-injurious behaviors, schizophrenia, or paranoid psychosis.

  • Growth
  • More rarely, they can present microcephaly (smaller head), intrauterine growth retardation, short stature, or macrocephaly (bigger head).

  • Malformations
    • SCongenital cardiopathy (9%) (Vanlerberghe et al, 2015)
    • Genital abnormalities (7%)
    • Recurrent infections (7%)
    • Cataracts (4%)
    • Hearing loss or impairment (4%)
    • Tracheoesophageal fistula (2%)
    • Omphalocele (2%)

    Heredity

    • Transmission: microdeletions are transmitted on an autosomal dominant mode. A carrier has a 50% probability to transmit this deletion to his descent.
    • In 51% of cases, a 15q11.2 microdeletion is inherited from a parent showing no symptoms. In 35% of cases, it is inherited from a parent presenting some clinical signs. In those two situations, the risk for other children to also inherit this deletion is of 50%.
    • 5-22% of the time, the 15q11.2 microdeletion happens de novo, which means during the conception of an affected person. The risk for siblings is in this case similar to the population risk.
    • Prenatal diagnosis: prenatal diagnosis is technically feasible by a chorionic villi sampling from 11 weeks of pregnancy or by an amniocentesis from 15 weeks of pregnancy. Few requests have been done for this condition because of the clinical variability and the impossibility to predict the manifestations.

    Duplication

    There is little information on the duplication and studies have not demonstrated for now that this genetic variation could contribute to developmental disorders.[Chaste et al 2014].

    Notes that little is know about the disease and this is why it's very important for studies to understand how this region can cause difficulties for some individuals carrying a certain rearrangement, and save others with the opposite one.

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