Systematische Identifizierung von Krankheitsgenen für angeborene Fehlbildungen des zentralen Nervensystems
Humangenetik
Zusammenfassung der Projektergebnisse
Congenital malformations of the central nervous system (CNS) can affect the brain and/or the neural tube (neural tube defects, NTDs). CNS malformations present isolated (non-syndromic) or non-isolated (syndromic) as part of a genetic syndrome. The most common brain malformations include agenesis of the corpus callosum, holoprosencephaly, various forms of septo-optic dysplasia, lissencephaly, other malformations of cerebral cortical development, neuronal migration disorders, intacranial cysts and lipomas, encephaloceles, congenital hydrocephalus, various forms of Chiari malformation and Dandy Walker syndrome, and schizencephaly. These various brain malformations might present with a broad clinical spectrum. The most common form of NTDs, myelomeningocele, is an open lesion in the caudal spine and contains dysplastic spinal cord, often resulting in a lack of neural function below the level of the defect. Affected patients usually have reduced ability to walk, or need the use of a wheelchair, have little or no bowel and/or bladder control, and require frequent surgical interventions to minimize the effects of hydrocephalus. Here we performed large scale exome and genome sequencing in affected singletons and case-parent trios. We identified several highly prioritized coding and non-coding variants / candidate genes which we envisage to functionally characterize in vivo using zebrafish as a vertebrate model system. Having performed functional studies in zebrafish of PLXNA1 and SHROOM4 we were able to support both genes as disease genes with PLXNA1 being annotated in OMIM as a novel disease gene for the novel syndrome "DWORSCHAK-PUNETHA NEURODEVELOPMENTAL SYNDROME (DWOPNED) (# 619955)”. Regarding our functional studies in zebrafish of TFAP2E we believe that here we have also provided compelling evidence for this gene to be considered a disease-gene for a novel complex neurodevelopmental syndrome.
Projektbezogene Publikationen (Auswahl)
-
Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies. Genetics in Medicine, 23(9), 1715-1725.
Dworschak, Gabriel C.; Punetha, Jaya; Kalanithy, Jeshurun C.; Mingardo, Enrico; Erdem, Haktan B.; Akdemir, Zeynep C.; Karaca, Ender; Mitani, Tadahiro; Marafi, Dana; Fatih, Jawid M.; Jhangiani, Shalini N.; Hunter, Jill V.; Dakal, Tikam Chand; Dhabhai, Bhanupriya; Dabbagh, Omar; Alsaif, Hessa S.; Alkuraya, Fowzan S.; Maroofian, Reza; Houlden, Henry; ... & Reutter, Heiko
-
X-linked variations inSHROOM4are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems. Journal of Medical Genetics, 60(6), 587-596.
Kolvenbach, Caroline M.; Felger, Tim; Schierbaum, Luca; Thiffault, Isabelle; Pastinen, Tomi; Szczepańska, Maria; Zaniew, Marcin; Adamczyk, Piotr; Bayat, Allan; Yilmaz, Öznur; Lindenberg, Tobias T.; Thiele, Holger; Hildebrandt, Friedhelm; Hinderhofer, Katrin; Moog, Ute; Hilger, Alina C.; Sullivan, Bonnie; Bartik, Lauren; Gnyś, Piotr; ... & Dworschak, Gabriel C.
