Mutation analysis of TGFBI and KRT12 in a case of concomitant
keratoconus and granular corneal dystrophy
Received: 12 December 2016 /Revised: 8 April 2017 / Accepted: 22 May 2017 / Published online: 31 May 2017
Springer-Verlag Berlin Heidelberg 2017
Purpose This study is to summarize the concurrent
keratoconus (KC) and granular corneal dystrophy (GCD) phe-
notype and identify the underlying genetic cause in a 23-year-
old male patient.
Methods A detailed family history and clinical data from the
patient and his parents were collected by ophthalmologic ex-
amination. The candidate genes were captured and sequenced
by targeted next-generation sequencing, and the results were
confirmed by Sanger sequencing.
Results The proband was clinically diagnosed as a case of
concurrent KC and GCD, which is a very rare presentation.
His father and grandmother were diagnosed as GCD in both
eyes. There was no character of KC in his father’s and grand-
mother’s eyes. A heterozygous TGFBI mutation in exon 4
(c.370G > A) was identified in the proband, which was
predicted to generate a missense mutation (p.R124H). The
mutation also existed in his father and grandmother. A hetero-
zygous KRT12 mutation in exon 8 (c.1456-1457ins GTA) was
identified in the proband, which was predicted to generate an
insert mutation and created a premature termination codon.
The mutation did not exist in his father and grandmother.
The two mutations did not exist in his mother and 200
unrelated normal controls.
Conclusions KC can co-exist with GCD. The missense mu-
tation (c.370G > A) in the TGFBI gene and insert mutation
(c.1456-1457ins GAT) in the KRT12 gene were identified in a
23-year-old male patient with concurrent KC and GCD.
Granular corneal dystrophy
Keratoconus (KC) is a bilateral, asymmetric, chronic progres-
sive ectasia of the cornea . The condition is characterized
by corneal steepening and distortion, thinning of the corneal
apex, and corneal scarring. Such changes cause progressive
myopia and irregular astigmatism. Its incidence is approxi-
mately 1 in 2000, and the prevalence is 54.5 per 100,000
. The etiology and pathogenesis of this disorder remain
unknown. Histologically, a keratoconic corneal stroma may
lose over 75% of normal thickness, causing extensive corneal
Granular corneal dystrophy (GCD) is a rare autosomal
dominant disorder featuring development of focal gray-white
opacities in the anterior stroma of the cornea. These opacities
slowly increase in number and progress into deeper stromal
layers . GCD type I is associated with the Arg555Trp and
Arg124Ser mutations . GCD type II, otherwise known as
Avellino corneal dystrophy, includes lattice deposits in addi-
tion to the characteristic granular opacities. GCD type II is
linked to the Arg124His mutation . We report the concom-
itant presentation of KC and GCD type II in a Chinese patient.
Genetic studies have focused mainly on corneal dystro-
phies and KC independently, but few reports have considered
these diseases in combination together. It seems that as there
are more cases of this combination in the literature [5–8], it is
* Peng Chen
State Key Laboratory Cultivation Base, Shandong Provincial Key
Laboratory of Ophthalmology, Shandong Eye Institute, Shandong
Academy of Medical Sciences, Qingdao, China
Department of Human Anatomy, Histology and Embryology,
Qingdao University, Qingdao, China
Graefes Arch Clin Exp Ophthalmol (2017) 255:1779–1786