Abstract:Rhombencephalosynapsis is an uncommon, but increasingly recognized, cerebellar malformation defined as vermian agenesis with fusion of the hemispheres. The embryologic and genetic mechanisms involved are still unknown, and to date, no animal models are available. In the present study, we used Agilent oligonucleotide arrays in a large series of 57 affected patients to detect candidate genes. Four different unbalanced rearrangements were detected: a 16p11.2 deletion, a 14q12q21.2 deletion, an unbalanced transloc… Show more
“…Several of these rearrangements are recurrently observed in cases of intellectual disability, such as 2.6 Mb-microdeletion of 22q11.21 (proximal deletion) corresponding to DiGeorge syndrome (Burnside, 2015), 16p11.2 microduplication that confers susceptibility to autism (Fernandez et al, 2010), 16p13.11 encompassing the NDE1 gene involved in brain neurogenesis and rhombencephalosynapsis (Bakircioglu et al, 2011;Démurger et al, 2013) and 15q11.2 microdeletion emerging as one of the most common cytogenetic abnormalities in intellectual disability and autism spectrum disorder (Butler, 2017). These deletions and duplications are thus at the origin of other neurodevelopmental disorders but are not sufficient to fully explain HPE.…”
Section: Chromosomal Abnormalities and Copy Number Variants In Hpementioning
Holoprosencephaly (HPE) is a complex genetic disorder of the developing forebrain characterized by high phenotypic and genetic heterogeneity. HPE was initially defined as an autosomal dominant disease, but recent research has shown that its mode of transmission is more complex. The past decade has witnessed rapid development of novel genetic technologies and significant progresses in clinical studies of HPE. In this review, we recapitulate genetic epidemiological studies of the largest European HPE cohort and summarize the novel genetic discoveries of HPE based on recently developed diagnostic methods. Our main purpose is to present different inheritance patterns that exist for HPE with a particular emphasis on oligogenic inheritance and its implications in genetic counseling.
“…Several of these rearrangements are recurrently observed in cases of intellectual disability, such as 2.6 Mb-microdeletion of 22q11.21 (proximal deletion) corresponding to DiGeorge syndrome (Burnside, 2015), 16p11.2 microduplication that confers susceptibility to autism (Fernandez et al, 2010), 16p13.11 encompassing the NDE1 gene involved in brain neurogenesis and rhombencephalosynapsis (Bakircioglu et al, 2011;Démurger et al, 2013) and 15q11.2 microdeletion emerging as one of the most common cytogenetic abnormalities in intellectual disability and autism spectrum disorder (Butler, 2017). These deletions and duplications are thus at the origin of other neurodevelopmental disorders but are not sufficient to fully explain HPE.…”
Section: Chromosomal Abnormalities and Copy Number Variants In Hpementioning
Holoprosencephaly (HPE) is a complex genetic disorder of the developing forebrain characterized by high phenotypic and genetic heterogeneity. HPE was initially defined as an autosomal dominant disease, but recent research has shown that its mode of transmission is more complex. The past decade has witnessed rapid development of novel genetic technologies and significant progresses in clinical studies of HPE. In this review, we recapitulate genetic epidemiological studies of the largest European HPE cohort and summarize the novel genetic discoveries of HPE based on recently developed diagnostic methods. Our main purpose is to present different inheritance patterns that exist for HPE with a particular emphasis on oligogenic inheritance and its implications in genetic counseling.
“…Autism was diagnosed in a patient with partial rhombencephalosynapsis (22). Chromosomal mutations in particular cases of rhombencephalosynapsis are associated with autism (23). Evidently, cerebellar malformation is responsible for autistic symptomatology.…”
“…Several studies have reported chromosomal rearrangements in patients with RES (Table II), though no recurrent copy number variants have emerged (Demurger et al, 2013; di Vera et al, 2008; Lespinasse et al, 2004; Pasquier et al, 2009; Ramocki et al, 2011; Truwit, Barkovich, Shanahan, & Maroldo, 1991). Partial RES was reported in one of 5 individuals with a de novo mutation in the CHAMP1 gene, but limited neuroimaging data were reported to substantiate this diagnosis (Hempel et al, 2015) and mutations in this gene have not been identified in other individuals with RES.…”
Rhombencephalosynapsis (RES) is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis. Subsets of patients also have other brain malformations such as midbrain fusion with aqueductal stenosis, characteristic craniofacial features (prominent forehead, flat midface, hypertelorism, ear abnormalities), and somatic malformations (heart, kidney, spine and limb defects). Similar to known genetic brain malformations, the RES cerebellar malformation is highly stereotyped, yet no genetic causes have not been identified. Here, we outline our current understanding of the genetic basis for RES, discuss limitations, and outline future approaches to identifying the causes of this fascinating brain malformation.
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