Unexpected Genetic Cause in Two Female Siblings with High Myopia and Reduced Visual Acuity

In daily life, myopia is a frequent cause of reduced visual acuity (VA) due to missing or incomplete optical correction. While the genetic cause of high myopia itself is not well understood, a significant number of cases are secondary to hereditary malfunctions or degenerations of the retina. The mechanism by which this occurs remains yet unclear. Two female siblings, 4 y and 2 y, respectively, from a consanguineous Pakistani family were referred to our department for reduced VA and strabismus. Both girls were highly myopic and hence were further examined using standard clinical tests and electroretinography (ERG). The latter confirmed confounded electrical coupling of photoreceptors and bipolar cells. Further inquiry and testing confirmed a similar condition for the father including impaired night vision, reduced VA, photophobia, and an equally characteristic ERG. Findings in the mother were unremarkable. Subsequent genetic analysis of autosomal recessive and X-linked genes for congenital stationary night blindness (CSNB) revealed a novel homozygous splice site mutation in CACNA1F in the two girls transmitted from both the father and the mother. While in males the above clinical constellation is a frequent finding, this report, to the authors’ knowledge, is the first demonstrating biallelic mutations at the CACNA1F locus in females.

Download Full-text

A Novel GALNT3 Mutation in a Pseudoautosomal Dominant Form of Tumoral Calcinosis: Evidence That the Disorder Is Autosomal Recessive

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-2302 ◽

2005 ◽

Vol 90 (4) ◽

pp. 2420-2423 ◽

Cited By ~ 117

Author(s):

Shoji Ichikawa ◽

Kenneth W. Lyles ◽

Michael J. Econs

Keyword(s):

Splice Site ◽

Autosomal Recessive ◽

Splice Site Mutation ◽

Tumoral Calcinosis ◽

Proper Function ◽

Single Mutation ◽

Recessive Trait ◽

Site Mutation ◽

Dominant Form ◽

Biallelic Mutations

Abstract Familial tumoral calcinosis is a rare metabolic disorder, characterized by ectopic calcification and hyperphosphatemia. Recently biallelic mutations in the GalNAc transferase 3 (GALNT3) gene were identified in two families with tumoral calcinosis. In the present study, we performed mutation analysis of the GALNT3 gene in a multigenerational family, which was originally described to have an autosomal dominant form of tumoral calcinosis. We identified a novel splice site mutation in intron 1 (IVS1–2a→t), likely leading to skipping of exon 2. The proband was a compound heterozygote for the splice site mutation and the previously reported nonsense mutation (484C→T; R162X). His affected maternal great uncle was homozygous for the splice site mutation. Biallelic mutations found in two generations demonstrated that the family had pseudoautosomal dominant inheritance, confirming that tumoral calcinosis is in fact an autosomal recessive trait. However, genetic and biochemical findings suggest that carriers of a single mutation may also manifest subtle biochemical abnormalities. Furthermore, coexpression of GALNT3 and fibroblast growth factor 23 (FGF23), a key regulator of phosphate homeostasis, in certain tissues suggests that O-glycosylation of FGF23 by GALNT3 may be necessary for proper function of FGF23.

Download Full-text

Novel splice site mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis: Case report and published work review

The Journal of Dermatology ◽

10.1111/1346-8138.14257 ◽

2018 ◽

Vol 45 (5) ◽

pp. 613-617 ◽

Cited By ~ 3

Author(s):

Yukari Mizukami ◽

Ryota Hayashi ◽

Daisuke Tsuruta ◽

Yutaka Shimomura ◽

Koji Sugawara

Keyword(s):

Case Report ◽

Splice Site ◽

Autosomal Recessive ◽

Splice Site Mutation ◽

Site Mutation ◽

Woolly Hair

Download Full-text

Characterization of a Putative Founder Mutation that Accounts for the High Incidence of Cystinosis in Brittany

Journal of the American Society of Nephrology ◽

10.1681/asn.v12102170 ◽

2001 ◽

Vol 12 (10) ◽

pp. 2170-2174

Author(s):

VASILIKI KALATZIS ◽

STÉPHANIE CHERQUI ◽

GENEVIÈVE JEAN ◽

BÉATRICE CORDIER ◽

PIERRE COCHAT ◽

...

Keyword(s):

Autosomal Recessive ◽

Founder Mutation ◽

Pcr Amplification ◽

Splice Site Mutation ◽

Autosomal Recessive Disorder ◽

Site Mutation ◽

Live Births ◽

Reverse Transcription Pcr ◽

High Incidence

Abstract. Cystinosis is an autosomal recessive disorder, characterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-900+24del27, which has only been detected in families from this region. Reverse transcription—PCR amplification of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are predicted to either severely truncate cystinosin or alter its topology, thus accounting for the severe phenotype of these individuals. The mutation 898-900+24del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cystinosis in Brittany.1

Download Full-text