De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype

Abstract

In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom's name was misspelled as Amron. The authors regret the error.

Mild prominence of the Sylvian fissure in a Bainbridge‐Ropers syndrome patient with a novel frameshift variant in ASXL3

“…Unlike previous reports, the patient had additional findings, that is, stereotypic movements (whispering face and hand-wringing), deep palmar creases, mild prominence of the Sylvian fissure with bitemporal hollowing, intrafissural venous plexus in the right parietal area, and scoliosis. Deep palmar creases were reported in SHAPNS by Shashi et al [14]. Our listed variations other than the ASXL3 gene and the DISC1 gene (Table S1) had not yet been established gene-phenotype relationships.…”

“…Unlike BOS, SHAPNS, and C syndrome, in BRPS, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, redundant skin, hirsutism, and "BOS posture" of elbow and wrist flexion are mild or absent [1,5,7,14]. The phenotype of the propositus is concordant with those of previous reports of BRPSsevere/profound mental retardation, hypotonia, delays in language acquisition, short stature of postnatal onset, craniofacial dysmorphism (prominent forehead, arched eyebrows, edematous periorbital region, short nose, anteverted nostrils, long philtrum, thin upper lip, full cheeks), and central nervous system abnormalities (hypoplastic body of the corpus callosum, mild atrophy of the cerebellar vermis, mild white matter loss of the frontal lobe).…”

“…BRPS is a unique disorder that has phenotypic overlap with Bohring-Opitz syndrome (BOS) (also known as Clike syndrome: MIM 605039), which is caused by heterozygous variant in the ASXL1 gene (MIM 612990) on chromosome 20q11, Shashi-Pena syndrome (SHAPNS) (MIM 617190), which is caused by heterozygous variant in the ASXL2 gene (MIM 612991) on chromosome 2p23, and C syndrome (Opitz trigonocephaly syndrome: MIM 211750), which is caused by heterozygous variant in the CD96 gene on chromosome 3q13 [1,5,7,14]. The features of C syndrome are, however, milder than those of BOS.…”

IRF2BPL Is Associated with Neurological Phenotypes

“…[8][9][10] More recently, new associations of genes with severe developmental phenotypes and neurodegeneration have been discovered. 11,12 This has been largely possible as a result of high-throughput sequencing methods such as next-generation sequencing (NGS), in conjunction with sequencing databases for control cohorts such as ExAC and gnomAD, [13][14][15][16][17][18][19][20][21] variant prediction, 22 model organism information (e.g., MARRVEL) 23 and crowdsourcing programs, such as GeneMatcher, 24 used for identifying additional cases. These tools have greatly promoted gene discovery and assisted in ascertaining the role of the candidate variants for disease.…”

Language and cognitive impairment associated to a novel p.Cys63Arg change in the MED13L gene

“…These genes are involved in brain development and function and their mutation give rise to some of the symptoms or features observed in our proband. For example, both ASXL1 and ASXL3 are candidates for Bohring-Opitz syndrome (#605039) and Bainbridge-Ropers syndrome (#615485), both with autosomal dominant inheritance and both entailing intellectual disability and dysmorphic features(Shashi et al 2016). However, the clinical profile of the patient and the nature of these variants leaded us to reclassify them as not relevant for genotype-to-phenotype correlations.…”