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.