INTRODUCTION
Primary congenital glaucoma (PCG) and Juvenile onset open angle glaucomas (JOAG) are generally monogenic, with genes having a strong biological effect playing a role in their pathogenesis. Apart fromMYOC, CYP1B1 and LTBP2 (Abu-Amero et al. 2011; Alsaif et al. 2019; Bayat et al. 2008; Chakrabarti et al. 2006; Chen et al. 2008; Gupta et al. 2018; Saeedi et al. 2018) newer genes associated with either form of glaucoma include the CPAMD8 , GPATCH,and EFEMP1 .(Ferre-Fernández et al. 2017; Mackay et al. 2015; Siggs et al. 2020) However, a large number of PCG and JOAG patients do not have a known gene mutation among these genes. (Knight et al. 2021) There are chromosomal loci where the putative genes associated with PCG and JOAG are still to be discovered. (Cascella et al. 2015) With the advent of next-generation sequencing, new gene discovery, especially for diseases where genetic variations have significant biological effect on disease causation, is being undertaken.
In this study, we describe a family of 3 siblings with GAPO syndrome, in whom we found two of them having congenital glaucoma. A WES analysis pointed towards the Transforming Growth Factor Beta Induced (TGFBI ) gene variant common to both siblings. Incidentally,TGFBI variants were also seen in three unrelated patients with JOAG, one of whom had familial granular corneal dystrophy.
GAPO syndrome is an extremely rare genetic disorder, with only about sixty cases reported to date. The ocular features of GAPO syndrome include puffy eyelids, sparse eyelash hair, poliosis, hypertelorism, ptosis, strabismus, nystagmus, megalocornea, keratoconus, keratopathy, optic atrophy, myelinated retinal nerve fiber layer and congenital glaucoma (buphthalmos) (Bozkurt et al. 2013). The diagnosis of GAPO is usually made early due to the characteristic premature ‘geriatric’ appearance of the patients, the presence of cardinal features like alopecia and pseudoanodontia, as well as the associated features like dwarfism, prominent supraorbital ridges, frontal bossing depressed nasal bridge, long philtrum, and a wide open anterior fontanelle. Late onset alopecia has also been frequently documented (Goloni-Bertollo et al. 2008; Rim & Marques-de-Faria 2005). Patients with GAPO have a reduced life span and usually die in their third or fourth decades of life due to generalized interstitial fibrosis of the lungs and atherosclerosis (Gagliardi et al. 1984; Mullaney et al. 1997).
The invariable consanguinity in these families with GAPO points towards an autosomal recessive mode of inheritance caused by mutations inANTXR1 on chromosomal position 2p14, a protein essential for intracellular actin assembly (Bayram et al. 2014; Stranecky et al. 2013). Defective production of this protein leads to altered cell adhesion properties leading to excessive deposition of extracellular matrix (ECM) secondary to reduced turnover, resulting in the various phenotypic features of this syndrome (Stranecky et al., 2013; Wajntal et al. 1990). While there are reports of the occurrence of glaucoma among patients with GAPO syndrome, (Goyal et al. 2014; Ilker et al. 1999; Kocabay & Mert 2009; Manouvrier-Hanu et al. 1987; Mullaney et al., 1997; Sayli & Gul 1993) it is not known whether mutations inANTXR1 gene itself or some other (glaucoma associated) genes, lead to the development of glaucoma. This report analyses the genetic background of two (out of three) children with GAPO syndrome and congenital glaucoma.