Whole-genome genetic diagnostics has changed the clinical landscape of pediatric and adolescent medicine. In this article, we review the history of clinical cytogenetics as the field has progressed ...from studying chromosomes prepared from cells squashed between 2 slides to the high-resolution, whole-genome technology in use today, which has allowed for the identification of numerous previously unrecognized microdeletion and microduplication syndromes. Types of arrays and the data they collect are addressed, as are the types of results that array comparative genomic hybridization studies may generate. Throughout the review, we present case stories to illustrate the familiar (Down syndrome) and the new (a never-before reported microdeletion on the long arm of chromosome 12).
BACKGROUNDThe etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new disease-associated genes and variant phenotypes associated ...with known genes. METHODSWe report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing. RESULTSWe identified a homozygous missense mutation in GM2A within a prominent block of homozygosity. This mutation is predicted to impair protein function. DISCUSSIONAlthough discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described GM2A patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways.
Zebrafish
bmp2a and
bmp2b mRNA expression in the developing median fins (caudal, anal, and dorsal) of late-stage larvae (>5 days post-fertilization) was analyzed by reverse transcriptase-PCR (RT-PCR) ...and in situ hybridization.
bmp2a is expressed in developing fin rays, while
bmp2b is expressed in developing fin rays, hypertrophic chondrocytes, and in the zone of segmentation (ZS) in developing anal and dorsal fin radials. This latter pattern of
bmp2b expression in the ZS mirrors tetrapod
bmp2 expression in developing joints. Additionally, both genes are expressed in neural and hemal arches and spines.
bmp2a is strongly expressed in the lens; lens
bmp2b expression is detected only weakly via RT-PCR.
Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement ...disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.
The etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new disease-associated genes and variant phenotypes associated with known ...genes.
We report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing.
We identified a homozygous missense mutation in GM2A within a prominent block of homozygosity. This mutation is predicted to impair protein function.
Although discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described GM2A patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways.
The dynamic expression of Gdf5 is described in the developing skeleton of the median fins of late-stage zebrafish, Danio rerio (6-45 days post-fertilization). In situ hybridization revealed ...expression in the mesenchyme between cartilage condensations of the endoskeletal supports of the dorsal, anal, and caudal fins. As development proceeds, the expression domains expand distally to surround tips of developing cartilages, consistent with a role in cartilage growth and differentiation. Gdf5 is later expressed in the segmenting regions of the dorsal and anal fin radials, which may indicate a role in segmentation. After growth to 7.5 mm, Gdf5 transcripts can no longer be detected in any of the median fins, nor is Gdf5 expression reinitiated in later development of the median fin skeleton.
Autism spectrum disorders (ASD) represent a common spectrum of developmental disabilities, sharing deficits in social interactions, communication and restricted interests or repetitive behaviors with ...difficult transitions. In this article, we review the history of the identification and classification of autism and the origin of the now widely-debunked autism/vaccine hypothesis. The differences between syndromal (complex) and non-syndromal (essential) autism are described and illustrated with case descriptions where appropriate. Finally, the evidence that autism is fundamentally a genetic disease is discussed, including family studies, the role of DNA copy number variation and known single gene mutations.
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