July brought about several customers having success with utilizing our VarSeq software. We saw publicized research regarding Axenfield-Reiger syndrome, Septo-Optic Dysplasia, and association of TGFBI variants. This range of customer usage displays the vast capabilities of VarSeq and the applications it can work with.

Axenfeld-Rieger syndrome: more than meets the eye

Background: Axenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition.
Methods: Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses.
Results: 128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS.
Conclusion: Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

Reis LM, Maheshwari M, Capasso J, et alAxenfeld-Rieger syndrome: more than meets the eyeJournal of Medical Genetics Published Online First: 26 July 2022. doi: 10.1136/jmg-2022-108646

Association of TGFBI variants with Congenital and Juvenile onset open angle glaucoma.

To describe a novel association of TGFBI variants with congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome as well as among unrelated cases of Juvenile onset open angle glaucoma (JOAG) along with the mechanistic impact of the variants on the protein. Methods: This study of one family of GAPO with congenital glaucoma and three unrelated patients of JOAG analysed a common link to glaucoma pathogenesis. We report ocular features of 3 girls with GAPO syndrome born of consanguineous marriage in a multi- generation consanguineous family. The proband (a 4year old girl) and her younger sibling (1year old girl) were operated for bilateral congenital glaucoma in both eyes. The elder sibling (10year old female) had features of GAPO syndrome without glaucoma. Results: A genetic evaluation using whole exome sequencing revealed a homozygous ANTXR1 mutation in all three affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense variant in the TGFBI gene was shared in the two siblings with congenital glaucoma and GAPO syndrome. We further found three other unrelated patients with JOAG with no known glaucoma causing gene mutations but having three different missense variants in the TGFBI gene. One of these JOAG patients had familial granular corneal dystrophy. Molecular dynamic simulations of the TGFBI and 3-D structural models of three of its variants showed sig­nificant alterations, which could influence TGFBI function. Conclusions: Variations in the TGFBI gene could have a possible role in the pathogenesis of congenital and Juvenile onset open angle glaucomas that needs further evaluation.

Viney Gupta, Arnav Panigrahi, Bindu Somarajan I, et al. Association of TGFBI variants with Congenital and Juvenile onset open angle glaucoma. Authorea. July 18, 2022. DOI: https://doi.org/10.22541/au.165812674.48680553/v1

Novel Genetic Diagnoses in Septo-Optic Dysplasia

Septo-optic dysplasia (SOD) is a developmental phenotype characterized by midline neuroradiological anomalies, optic nerve hypoplasia, and pituitary anomalies, with a high degree of variability and additional systemic anomalies present in some cases. While disruption of several transcription factors has been identified in SOD cohorts, most cases lack a genetic diagnosis, with multifactorial risk factors being thought to play a role. Exome sequencing in a cohort of families with a clinical diagnosis of SOD identified a genetic diagnosis in 3/6 families, de novo variants in SOX2, SHH, and ARID1A, and explored variants of uncertain significance in the remaining three. The outcome of this study suggests that investigation for a genetic etiology is warranted in individuals with SOD, particularly in the presence of additional syndromic anomalies and when born to older, multigravida mothers. The identification of causative variants in SHH and ARID1A further expands the phenotypic spectra associated with these genes and reveals novel pathways to explore in septo-optic dysplasia. 

Reis, L.M.; Seese, S.; Maheshwari, M.; Basel, D.; Weik, L.; McCarrier, J.; University of Washington Center for Mendelian Genomics; Semina, E.V. Novel Genetic Diagnoses in Septo-Optic Dysplasia. Genes 2022, 13, 1165. https://doi.org/10.3390/genes13071165