Further defining the critical genes for the 4q21 microdeletion disorder

Abstract

4q21 microdeletion syndrome (MIM: 613509) is a new genomic disorder characterized by intellectual disability, absent or severely delayed speech, growth retardation, hypotonia, variable brain malformation, and facial dysmorphism. The critical genes had been proposed based on an overlapping 1.37 Mb genomic region. No further refinement has been done since year 2010. Here, we present three cases with 4q21 deletion identified by clinical chromosomal microarray analysis. One of the cases have a de novo 761 kb deletion which is the smallest deletion ever reported at this locus. It provides an opportunity to further define the critical regions/genes associated with specific features of the 4q21 microdeletion syndrome. The evidence support the notion that PRKG2 and RASGEF1B are critical genes for intellectual disability and speech defect, and the heterogeneous nuclear ribonucleoprotein HNRNPD and HNRNPDL (previously known as HNRPDL) genes are associated with growth retardation and hypotonia. © 2016 Wiley Periodicals, Inc.

Williams Syndrome, Human Self-Domestication, and Language Evolution

“…The hemyzigosis of GTF2IRD1 and GTF2I has been hypothesized to contribute as well to the cognitive and language features of WS (Vandeweyer et al, 2012), because it gives rise to motor dysfunctions and vocalization alterations (Howard et al, 2012). Regarding the candidates for domestication belonging to this network, it is worth highlighting that PRKG2 has been associated with dwarfism in livestock (Boegheim et al, 2017), but also to spatial memory and motor coordination deficits in mice (Wincott et al, 2013), and to intellectual disability and speech problems in humans (Bonnet et al, 2010; Hu et al, 2017). Signaling through Prkg2 in the amygdala is critical for auditory-cued fear memory and long-term potentiation (Paul et al, 2008).…”

Williams syndrome, human self-domestication, and language evolution

“…The hemyzigosis of GTF2IRD1 and GTF2I has been hypothesized to contribute as well to the cognitive and language features of WS (Vandeweyer et al, 2012), because it gives rise to motor dysfunctions and vocalization alterations (Howard et al, 2012). Regarding the candidates for domestication belonging to this network, it is worth highlighting that PRKG2 has been associated with dwarfism in livestock (Boegheim et al, 2017), but also to spatial memory and motor coordination deficits in mice (Wincott et al, 2013), and to intellectual disability and speech problems in humans (Bonnet et al, 2010;Hu et al, 2017). Signaling through Prkg2 in the amygdala is critical for auditory-cued fear memory and long-term potentiation (Paul et al, 2008).…”

Loss of cGMP-dependent protein kinase II alters ultrasonic vocalizations in mice, a model for speech impairment in human microdeletion 4q21 syndrome

“…The copyright holder for this preprint this version posted January 7, 2021. ; https://doi.org/10.1101/2021.01.06.425531 doi: bioRxiv preprint 6 which is important for learning and memory [12,13,19]. In fact, cGKII knockout (KO) mice exhibit severe impairment in hippocampus-dependent learning and memory [20,21], which is relevant to mental retardation found in human microdeletion 4q21 syndrome [1,2]. Taken together, loss of the cGKII gene may underlie neurological symptoms in microdeletion 4q21 syndrome, which includes intellectual disability and speech defects.…”

“…Speech production involves multiple brain regions as well as neuronal control of muscles in the lung, larynx, and pharynx [23][24][25]. Significantly, speech defects are one of the primary characteristics of the human microdeletion 4q21 syndrome, but the mechanisms underlying speech delay are unknown [1,2]. Rodents communicate through the use of high frequency, ultrasonic vocalizations (USVs), and the specific frequency emitted is dependent on the context, including male-female interactions, juvenile social interactions, and in mother-infant interactions [22,[26][27][28].…”