NDD. Family-based (trio) exome sequencing has become the standardized method for identifying genetic etiologies that cause neurodevelopmental disorders. De novo variants have been responsible for the majority of pathogenic genetic findings, although the landscape of genetic disorders overall is highly heterogeneous. In a recently published study, the authors assessed variant classification to identify new molecular diagnoses and factors influencing the likelihood of receiving a diagnosis. The study reported a diagnostic yield of over 41%, highlighting 60 new genes associated with developmental disorders. The authors also emphasized the importance of structured and detailed phenotypic information for improving variant interpretation. This blog post provides a brief review of their publication in the context of improving diagnostic yield using a phenotypically driven approach in rare diseases.
Four things to know about ATP1A3 in 2023
ATP1A3. We recently posted about ATP1A3, a gene implicated in alternation hemiplegic of childhood, epilepsy, and other phenotypes. Today, we have added a new gene page going into more depth on this fascinating gene. Below are the five highlights to know about ATP1A3.
Chromosome 15q11-13: Part 2, a clinical perspective
One region, three disorders. The following blogpost serves as a partner to this week’s earlier post on the genomic idiosyncrasies of the 15q11-13 region. We hope that the discussion of the clinical aspects of disorders rooted in this region will further illustrate the vast complexity of the genome. Below we describe the three clinical syndromes associated with this region.
Chromosome 15q11-13: one region, many disorders
Cytogenetics. 15q11-13 can be an intimidating region, even for many seasoned genetics professionals. Several factors contribute to this, including a complex genomic architecture, genomic imprinting, an acrocentric chromosome, and several genes critical to neurological function. For today’s blog post, we’ll try to unravel some of its complexity to make interpretation of copy number variants (CNVs) in this area clearer.
ATP1A2: more than a fraternal twin
ATP1A2. We have previously written about ATP1A3, one of the neuronal ATPases, which, together with ATP1A2, actively works to maintain the electrochemical gradient across cell membranes. In our previous post, we likened ATP1A3 to Sisyphus, who was punished by the gods to spend eternity exerting his strength to push a boulder up a hill, only for the boulder to roll back down, over and over again. Similarly, the ATPases utilize energy (ATP) to transport Na+ out of the cell and K+ into the cell, even while other voltage-gated channels effortlessly open to allow Na+ and K+ to move in the opposite direction, forcing the boulder back down the hill. However, from another perspective we can see that far from being Sisyphus, the ATPases are the noblest of facilitators, proudly maintaining the membrane electrochemical gradient in order to enable all other cell processes to function. If you will allow me further anthropomorphization of submicroscopic proteins – far from being inconsiderate to the task of the ATPases, our voltage-gated Na+, K+, and Ca++ channels are reliant on these stoic transporters to get their jobs done. It is because of the electrochemical gradient that cells are able to propagate action potentials down an axon, signal axon terminals to release neurotransmitters, and continue to send electrochemical signals on to subsequent cells. Both ATP1A2 and ATP1A3 code for subunits of the Na+-K+ ATPase, where ATP1A2 codes for the α2 subunit and ATP1A3 for the α3 subunit. Both ATP1A3 and ATP1A2 are expressed in neurons during embryonal brain development, and while ATP1A3 remains neuronal postnatally, ATP1A2 is relegated to the glial cells postnatally and into adulthood. In addition to their role in active ion transport, Na+-K+ ATPases are thought to play a part in regulating signaling pathways and gene transcription. Given its localization to astrocytes, which act as a so-called “glutamate sink” to prevent glutamate excitotoxicity within the synapse, ATP1A2 is thought to be critical for the process of glutamate clearance and prevention of excitotoxicity (Du et al 2020).
Expanding access: the role of the epilepsy nurse practitioner
Nurse practitioners. Last month was nurses’ month – yes that’s correct, we have been upgraded from the previous nurses’ week. As the month comes to an end, I would like to briefly reflect on the role of the nurse practitioner (NP) in the epilepsy field.
GRIA-related disorders – a different side of glutamate receptor dysfunction
GRIA genes. This is the first time we are describing GRIA genes on this blog. GRIA genes, which include GRIA1, GRIA2, GRIA3, and GRIA4, encode the AMPA receptor, one of the two key channels in the process of glutamate neurotransmission. While GRIN genes, which encode the NMDA receptor, have been characterized much more extensively in the literature, GRIAs remain relatively under-characterized, even though their protein products are involved in a similar molecular process in the post-synapse in modulating excitatory synaptic transmission. Here, we provide a brief overview of the genetic and phenotypic range of GRIA-related disorders.
SYT1-related disorder: a neurodevelopmental SNAREopathy
SYT1. To continue our series on SNAREopathies—developmental disorders caused by genes encoding proteins involved in the SNARE complex—we next provide a brief overview of SYT1-related disorders. The gene SYT1 encodes synaptotagmin-1 (SYT1), which belongs to the group of synaptotagmin proteins that are essential for neurotransmission. Disease-causing mutations in SYT1 have a spectrum of clinical presentations ranging in severity and phenotypic complexity but also with certain unifying features, making SYT1-related disorders a complex neurodevelopmental SNAREopathy.
No sample left behind
Clinical Research Coordinator. My job as a Clinical Research Coordinator (CRC) is to coordinate the process of obtaining samples and entering them into our database and then seeing that they get to the lab to be processed and stored for research. That is the definition – but what we do is so much more. We approach families, and our first impression sets the tone for their willingness (or their not-so-willingness) to participate. Here is our guide to what it takes to be a CRC.
ATP1A3: Sisyphus with a purpose
ATP1A3. The ATPases are the “Sisphyean” workhorses of cells, perpetually bound to utilize energy generated by mitochondria to pump ions across cell membranes. This is essential to the maintenance of the intra/extracellular electrochemical gradient. ATP1A3 codes for the α3 subunit of the Na+-K+ ATPase, which utilizes ATP to actively transport sodium out of the cell and potassium into the cell. In the brain, this gradient is critical for cell signaling and for maintaining electrochemical stability, enabling cell excitation and action potential propagation. Both ATP1A3 and one of its counterparts, ATP1A2, are expressed in neurons during embryonal brain development, and ATP1A3 is also thought to contribute to regulation of non-ionic neuronal transporters and receptors. However, whereas ATP1A2 is primarily expressed in glial cells postnatally and into adulthood, ATP1A3 continues to be expressed primarily in neurons, with particular enrichment in excitatory neurons. Here is a brief overview of the clinical spectrum of ATP1A3-related disorders.
