Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype

Abstract

Whole‐exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2‐related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients. This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2‐related disorder and the Angelman‐/Rett‐/Pitt‐Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2‐related disorder.

Response to Steroids in IQSEC2-Related Encephalopathy Presenting with Rett-Like Phenotype and Infantile Spasms

“…IQSEC2 gene mutations were previously reported in families with X-linked ID. 2,3 Recent literature has shown that IQSEC2 mutations cause a neurodevelopmental disorder with many features starting early in life. [3][4][5]7 The IQSEC2 gene is placed on chromosome Xp11.22 and its product, the BRAG1 protein, is located on the excitatory synapse as a part of the Nmethyl-D-aspartic acid receptor complex, and plays a role in synaptic plasticity and dendritic spine formation.…”

“…2,3 Recent literature has shown that IQSEC2 mutations cause a neurodevelopmental disorder with many features starting early in life. [3][4][5]7 The IQSEC2 gene is placed on chromosome Xp11.22 and its product, the BRAG1 protein, is located on the excitatory synapse as a part of the Nmethyl-D-aspartic acid receptor complex, and plays a role in synaptic plasticity and dendritic spine formation. 8 These proteins are required for trafficking of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptors from the surface of hippocampal neurons, thus playing an important role in learning and memory processes.…”

“…Other uncommon associations reported are posterior urethral valve and precocious puberty. 3 Females generally have milder symptoms in comparison to males with this disorder. 3,4 Imaging of the brain may be normal or show delayed myelination, thin corpus callosum, and cortical atrophy.…”

“…2 However, recent data point to the occurrence of syndrome with ID, epilepsy, ASD, hypotonia, speech delay, microcephaly, and facial dysmorphism, which is now recognized as part of the phenotypic spectrum of IQSEC2 variants. [3][4][5] Here is the case summary of a child whose clinical features add to the growing spectrum of IQSEC2-related encephalopathy and highlight the role of steroids in IQSEC2. To the best of our knowledge, this is the first case reported from India.…”

Phenotypic similarity for rare disease: Ciliopathy diagnoses and subtyping

“…The challenges such as incompleteness, inaccuracy and complexity have been much discussed (Hripcsak and Albers, 2013). Many studies of deep phenotyping focused on a set of phenotypic features defined based on expert knowledge of specific diseases or medical issues (Kopf et al, 2018;Peron et al, 2018;Radley et al, 2019) (Greene et al, 2016). In our study, the EHRs are in French language, thus the annotation is achieved with UMLS French (SAP=FRE) in our data warehouse.…”