The segregation of different submicroscopic imbalances underlying the clinical variability associated with a familial karyotypically balanced translocation
Abstract:BackgroundAbout 7 % of karyotypically balanced chromosomal rearrangements (BCRs) are associated with congenital anomalies due to gene or regulatory element disruption, and cryptic imbalances on rearranged chromosomes. Rare familial BCRs segregating with clinical features are a powerful source for the identifying of causative genes due to the presence of several affected carriers.Case presentationWe report on a karyotypically balanced translocation t(2;22)(p13;q12.2) associated with variable learning disabiliti… Show more
“…16 For amplification and Sanger sequencing of the breakpoints to sequence level, the forward and reverse primer pairs F1_der9 5′-TGACCAC ATTGCAAACCATT-3′; R2_der9 5′-TTGTTTGTGGGCAAATTTCA-3′ and R1_der19 5′-AATACACTTTATGTGGATGTGT-3′; F2_der19 5′-CGTGGA AGCCTCCTCAGATA-3′ were used to define the chromosomes 9 and 19 breakpoints.…”
Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C4T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T4C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.
“…16 For amplification and Sanger sequencing of the breakpoints to sequence level, the forward and reverse primer pairs F1_der9 5′-TGACCAC ATTGCAAACCATT-3′; R2_der9 5′-TTGTTTGTGGGCAAATTTCA-3′ and R1_der19 5′-AATACACTTTATGTGGATGTGT-3′; F2_der19 5′-CGTGGA AGCCTCCTCAGATA-3′ were used to define the chromosomes 9 and 19 breakpoints.…”
Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C4T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T4C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.
“… Figure 4 Diseases and disorders associated with centrosome cohesion defects. The diagram summarizes diseases (pink panels) and disorders (grey panels) associated with alterations of genes encoding known centrosome cohesion proteins (green panels) [ 86 – 90 , 92 , 95 , 112 , 117 , 119 , 120 , 123 – 126 , 131 , 133 , 147 ]. …”
Section: Centrosome Cohesion In Developmentmentioning
confidence: 99%
“…Consistent with these complex scenarios of human genetic disorders, mutations in some centrosome linker genes have been identified in diseases associated with other genes. For example, mutations in CEP68, CCDC102B and CNTLN along with additional gene alterations, were identified in microdeletion syndrome, myopic maculopathy and Alzheimer's disease, respectively [123][124][125]. Likewise, CROCC mutation was also found in neuroblastoma patients [126].…”
Section: Centrosome Cohesion Associated With Other Genetic Disordersmentioning
The centrosome, consisting of centrioles and the associated pericentriolar material, is the main microtubule-organizing centre (MTOC) in animal cells. During most of interphase, the two centrosomes of a cell are joined together by centrosome cohesion into one MTOC. The most dominant element of centrosome cohesion is the centrosome linker, an interdigitating, fibrous network formed by the protein C-Nap1 anchoring a number of coiled-coil proteins including rootletin to the proximal end of centrioles. Alternatively, centrosomes can be kept together by the action of the minus end directed kinesin motor protein KIFC3 that works on interdigitating microtubules organized by both centrosomes and probably by the actin network. Although cells connect the two interphase centrosomes by several mechanisms into one MTOC, the general importance of centrosome cohesion, particularly for an organism, is still largely unclear. In this article, we review the functions of the centrosome linker and discuss how centrosome cohesion defects can lead to diseases.
“…Missense, frameshift indels, and nonsense mutations in MEGF10 cause respiratory distress usually induced by diaphragmatic paralysis. Affected individuals frequently become ventilator dependent or die secondary to respiratory failure [17].…”
Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of such disorders, early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD, OMIM: 614399, MIM: 612453), is a rare autosomal recessive disorder caused by biallelic mutations (at homozygous or compound heterozygous status) in MEGF10 (multiple epidermal growth factor-like domains protein family). Here, we report two unrelated patients, who were born to consanguineous parents, having two novel MEGF10 deleterious variants. Interestingly, the presence of MEGF10 associated EMARDD has not been reported in Saudi Arabia, a highly consanguineous population. Moreover, both variants lead to a different phenotypic onset of mild and severe types. Our work expands phenotypic features of the disease and provides an opportunity for genetic counseling to the inflicted families.
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