1: Ophthalmic Genet. 2012 Jan 24; [Epub ahead of print] 

Homozygosity mapping in an anophthalmic pedigree provides evidence of additional
genetic heterogeneity.

Khorshidi A, Russell L, Bamforth S, Drummond G, Johnson R, Lehmann OJ.

Department of Medical Genetics, University of Alberta ,  Edmonton ,  Canada.

Purpose: Anophthalmia is a heterogeneous developmental disorder characterized by
absent eyes whose diverse etiology encompasses chromosomal and monogenic
aberrations, as well as environmental causes. Since the molecular basis has been
defined in only a small proportion of cases and extending this offers potential
to enhance understanding of key steps in ocular development, a consanguineous
anophthalmic pedigree was investigated using homozygosity mapping.   Methods:
DNA samples from six individuals, two anophthalmic, were genotyped with an array
featuring approximately 620,000 single nucleotide polymorphisms (SNPs) in order
to identify homozygous or copy number variant (CNV) regions. Candidate genes
located in regions of identity by descent (IBD) defined by homozygosity mapping
were subsequently screened by direct sequencing.   Results: Genotyping
identified five homozygous intervals (4q26-28.1, 13q12.11, 14q22.1-22.2,
15q26.2-26.3 and 19q13.12) larger than 1 Mb that do not correspond with the
known loci and which contain a total of 205 annotated genes. No CNVs were
identified that segregated with the disease phenotype, and sequencing of five
candidate genes (PRDM5, FGF2, SOS2, POU2F2 and CIC) did not identify any
mutations.   Conclusions: Although constrained by the pedigree's size, the
homozygosity mapping approach employed in this study extends the locus
heterogeneity of anophthalmia. The results indicate that a novel molecular cause
remains to be determined in this pedigree with the causative gene likely located
within one of the five IBD regions.

PMID: 22273394  [PubMed - as supplied by publisher]

2: Ophthalmic Genet. 2012 Jan 9; [Epub ahead of print] 

Phenotype-genotype Correlation in Potential Female Carriers of X-linked
Developmental Cataract (Nance-Horan Syndrome).

Khan AO, Aldahmesh MA, Mohamed JY, Alkuraya FS.

Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital , 
Riyadh ,  Saudi Arabia.

Purpose: To correlate clinical examination with underlying genotype in
asymptomatic females who are potential carriers of X-linked developmental
cataract (Nance-Horan syndrome).   Methods: An ophthalmologist blind to the
pedigree performed comprehensive ophthalmic examination for 16 available family
members (two affected and six asymptomatic females, five affected and three
asymptomatic males). Facial features were also noted. Venous blood was collected
for sequencing of the gene NHS.   Results: All seven affected family members had
congenital or infantile cataract and facial dysmorphism (long face, bulbous
nose, abnormal dentition). The six asymptomatic females ranged in age from 4-35
years old. Four had posterior Y-suture centered lens opacities; these four also
exhibited the facial dysmorphism of the seven affected family members. The fifth
asymptomatic girl had scattered fine punctate lens opacities (not centered on
the Y-suture) while the sixth had clear lenses, and neither exhibited the facial
dysmorphism. A novel NHS mutation (p.Lys744AsnfsX15 [c.2232delG]) was found in
the seven patients with congenital or infantile cataract. This mutation was also
present in the four asymptomatic girls with Y-centered lens opacities but not in
the other two asymptomatic girls or in the three asymptomatic males (who had
clear lenses).   Conclusions: Lens opacities centered around the posterior
Y-suture in the context of certain facial features were sensitive and specific
clinical signs of carrier status for NHS mutation in asymptomatic females. Lens
opacities that did not have this characteristic morphology in a suspected female
carrier were not a carrier sign, even in the context of her affected family
members.

PMID: 22229851  [PubMed - as supplied by publisher]

3: Ophthalmic Genet. 2012 Jan 9; [Epub ahead of print] 

Phenotypic and genetic spectrum of Danish patients with ABCA4-related
retinopathy.

Duno M, Schwartz M, Larsen PL, Rosenberg T.

Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital
,  Denmark.

Background: Pathogenic variations in the ABCA4 gene were originally recognized
as genetic background for the autosomal recessive disorders Stargardt disease
and fundus flavimaculatus, but have expanded to embrace a diversity of retinal
diseases, giving rise to the new diagnostic term, ABCA4-related retinopathy.
Diagnostic genotyping of ABCA4 is complicated by the large size of the gene and
the existence of approximately 600 known pathogenic variations, along with
numerous rare polymorphisms. A commercial diagnostic array-based assay has been
developed targeting known mutations, however a conclusive genetic diagnosis must
rely on a comprehensive genetic screening as the mutation spectrum of
ABCA4-related retinopathies continues to expand.   Material and methods: Among
161 patients with a Stargardt-related phenotype previously assessed with the
commercial ABCA4 mutation microarray, we analyzed the ABCA4 gene with
High-resolution melting (HRM) in patients in whom the array analysis identified
either a heterozygous mutation (n = 50) or no mutation (n = 30).   Results: The
HRM method detected each of the already known mutations and polymorphisms. We
identified the second ABCA4 mutation in 31 of 50 heterozygous patients (62%).
Several novel mutations were identified of which four were identified multiple
times. The recurrent novel mutations were subsequently assessed among the 30
patients with possible ABCA4-related diseases, previously found to be negative
for known ABCA4 mutations by array analysis. In total, 30 different mutations
were identified of which 21 have not been described before.   Conclusion:
Scandinavian patients with ABCA4-related retinopathy appear to have a distinct
mutation spectrum, which can be identified in patients of diverse clinical
phenotypes.

PMID: 22229821  [PubMed - as supplied by publisher]

4: Ophthalmic Genet. 2012 Jan 9; [Epub ahead of print] 

Axenfeld-Rieger Spectrum in a Patient with 45,X Turner Syndrome.

Abdalla EM, Nabil KM.

Department of Human Genetics, Medical Research Institute, Alexandria University
,  Egypt.

Purpose: To report the presence of Axenfeld-Rieger spectrum in a case of 45,X
Turner syndrome.   Design: Non-interventional case report.   Methods: A
13-year-old girl underwent complete genetic clinical evaluation comprising
detailed family history taking with pedigree construction in addition to a
thorough clinical examination and a number of investigations. A cytogenetic
study, molecular testing for hidden Y-chromosome material, and a full
ophthalmological assessment including slit lamp examination were also performed.
  Results: Physical examination revealed typical features of Turner syndrome:
short stature, webbing of the neck with low posterior hairline, widely spaced
nipples and lack of development of secondary sexual characteristics. Abdominal
and pelvic ultrasound showed a horse-shoe kidney with double ureter, a
hypoplastic uterus and bilateral streak ovaries. Mitral regurgitation was
diagnosed on echocardiography. Chromosomal analysis revealed a 45,X Turner
syndrome karyotype while the molecular study failed to demonstrate any occult Y
chromosome derivative. The ophthalmological assessment revealed sclerocornea and
Axenfeld anomaly with synechia.   Conclusion: Few reported cases in the
literature describe the coexistence of Axenfeld-Rieger spectrum and Turner
syndrome. Our study adds to the evidence that ocular problems occur frequently
in Turner syndrome. A routine ophthalmologic examination is recommended early in
Turner syndrome to diagnose and treat confirmed abnormalities. Conversely,
general examination and chromosomal analysis should be indicated in patients
presenting with anterior chamber dysgenesis.

PMID: 22229795  [PubMed - as supplied by publisher]

5: Ophthalmic Genet. 2012 Jan 4; [Epub ahead of print] 

Association of p.P347L in the rhodopsin gene with early-onset cystoid macular
edema in patients with retinitis pigmentosa.

Kim C, Chung H, Yu HG.

Department of Ophthalmology, Seoul National University College of Medicine , 
Seoul ,  Korea.

Purpose: To describe early-onset cystoid macular edema (CME) in a family with
retinitis pigmentosa (RP) due to the p.P347L in the rhodopsin gene (RHO).  
Methods: All affected family members, including a 44-year-old mother and four
children in their teens (two daughters, 17 and 15 years old, and two sons, 13
and 11 years old), have a mutation of p.P347L in RHO. Funduscopy, Goldmann
perimetry, spectral domain optical coherence tomography (SD-OCT) and
electroretinogram (ERG) were performed in all affected members to assess the
retinal anatomy and function.   Results: The mother had very poor visual acuity
of light perception in both eyes, and marked foveal atrophy was observed via
SD-OCT. Although the macular appearance in the funduscopy looked unremarkable in
the four children, SD-OCT revealed bilateral CME in all the children. The rod
response in ERG was extinguished and the cone response was decreased in all
children.   Conclusion: The results present the possibility that CME in RP
patients may be associated with a specific genotype such as the p.P347L in RHO.
We speculate that the severe visual prognosis of this mutation may be related to
early-onset CME, as shown in this family. However, further investigation in more
RP patients with this mutation and CME will be needed.

PMID: 22217031  [PubMed - as supplied by publisher]

6: Ophthalmic Genet. 2012 Jan 4; [Epub ahead of print] 

Identification of the p. R116H mutation in a Chinese family with novel variable
cataract phenotype: Evidence for a mutational hot spot in alphaA-crystallin
gene.

Wang B, Wang KJ, Zhu SQ, Wang J, Ma X.

National Research Institute for Family Planning ,  Beijing ,  China.

Purpose: To report the recurrent p.R116H mutation in the alphaA-crystallin gene
(CRYAA) which causes a novel variable cataract phenotype, and to determine
whether this mutation represents a mutational hot spot.   Methods: Family
history and clinical data were recorded. The genomic DNA was extracted from
peripheral blood leukocytes. Microsatellite markers at loci considered to be
associated with autosomal dominant cataracts were selected and genotyped for
two-point linkage analysis. Direct sequencing was performed to identify the
disease-causing mutation. Haplotype analysis was constructed to compare the
affected haplotype in this family and in another Chinese family previously
reported by us.   Results: Clinical features of cataract in this family were
asymmetric in two eyes of some affected subjects. Evidence of linkage was
obtained with marker D21S1411 (logarithm of odds [LOD] score [Z] = 2.42,
recombination fraction [theta] = 0.0). Sequencing of the candidate CRYAA gene
revealed a single base alteration c.347 G > A in exon 3, which resulted in the
substitution of highly conserved arginine by histidine at codon 116 (p.R116H).
This mutation co-segregated with all affected individuals and was not observed
in unaffected family members or 100 normal unrelated individuals. The
comparative haplotype analysis showed that the affected haplotypes in the two
families were different.   Conclusions: This study identified a novel
cataract-microcornea phenotype caused by the recurrent mutation p.R116H in
CRYAA, and suggested that this mutation site is not likely the consequence of a
founder effect, but probably a result of a mutational hot spot.

PMID: 22216983  [PubMed - as supplied by publisher]