ABSTRACT
BACKGROUND: Hereditary ophthalmic pathology is a genetically heterogeneous group of diseases that occur either as an isolated eye disorder or as a symptom of hereditary syndromes (chromosomal or monogenic). Thus, a diagnostic search in some cases of ophthalmic pathology can be time- and cost-consuming. The most challenging situation can arise when prenatal diagnosis is needed during an ongoing pregnancy. CASE PRESENTATION: A family was referred to the Research Centre for Medical Genetics (RCMG) for childbirth risk prognosis at 7-8 week of gestation because a previous child, a six-year-old boy, has congenital aniridia, glaucoma, retinal detachment, severe psychomotor delay, and lack of speech and has had several ophthalmic surgeries. The affected child had been previously tested for PAX6 mutations and 11p13 copy number variations, which revealed no changes. Considering the lack of pathogenic changes and precise diagnosis for the affected boy, NGS sequencing of clinically relevant genes was performed for the ongoing pregnancy; it revealed a novel hemizygous substitution NM_000266.3(NDP):c.385G > T, p.(Glu129*), in the NDP gene, which is associated with Norrie disease (OMIM #310600). Subsequent Sanger validation of the affected boy and his mother confirmed the identified substitution inherited in X-linked recessive mode. Amniotic fluid testing revealed the fetus was hemizygous for the variant and lead to the decision of the family to interrupt the pregnancy. Complications which developed during the termination of pregnancy required hysterectomy due to medical necessity. CONCLUSIONS: Clinical polymorphism of hereditary ophthalmic pathology can severely complicate establishment of an exact diagnosis and make it time- and cost-consuming. NGS appears to be the method-of-choice in complicated cases, and this could substantially hasten the establishment of a diagnosis and genetic risk estimation.
Subject(s)
Blindness/congenital , Eye Proteins/genetics , Genetic Diseases, X-Linked/diagnosis , Nerve Tissue Proteins/genetics , Nervous System Diseases/diagnosis , Prenatal Diagnosis/methods , Retinal Degeneration/diagnosis , Spasms, Infantile/diagnosis , Amino Acid Substitution , Blindness/diagnosis , Blindness/genetics , Eye/pathology , Female , Genes, X-Linked/genetics , Genetic Diseases, X-Linked/genetics , Humans , Nervous System Diseases/genetics , Pregnancy , Retinal Degeneration/genetics , Spasms, Infantile/genetics , Exome SequencingABSTRACT
Purpose: To evaluate the phenotypic spectrum of autosomal recessive RP1-associated retinal dystrophies and assess genotypic associations. Methods: A retrospective multicenter study was performed of patients with biallelic RP1-associated retinal dystrophies. Data including presenting symptoms and age, visual acuity, kinetic perimetry, full field electroretinogram, fundus examination, multimodal retinal imaging, and RP1 genotype were evaluated. Results: Nineteen eligible patients from 17 families were identified and ranged in age from 10 to 56 years at the most recent evaluation. Ten of the 21 unique RP1 variants identified were novel, and mutations within exon 2 accounted for nearly half of alleles across the cohort. Patients had clinical diagnoses of retinitis pigmentosa (13), cone-rod dystrophy (3), Leber congenital amaurosis (1), early-onset severe retinal dystrophy (1), and macular dystrophy (1). Macular atrophy was a common feature across the cohort. Symptom onset occurred between 4 and 30 years of age (mean 14.9 years, median 13 years), but there were clusters of onset age that correlated with the effects of RP1 mutations at a protein level. Patients with later-onset disease, including retinitis pigmentosa, had at least one missense variant in an exon 2 DCX domain. Conclusions: Biallelic RP1 mutations cause a broad spectrum of retinal disease. Exon 2 missense mutations are a significant contributor to disease and can be associated with a considerably later onset of retinitis pigmentosa than that typically associated with biallelic RP1 mutations.
Subject(s)
Microtubule-Associated Proteins/genetics , Retinal Dystrophies/genetics , Adolescent , Adult , Alleles , Child , Cohort Studies , Cone-Rod Dystrophies/genetics , DNA Mutational Analysis , Electroretinography , Eye Diseases, Hereditary/genetics , Female , Genotype , Humans , Leber Congenital Amaurosis/genetics , Macular Degeneration/genetics , Male , Middle Aged , Mutation , Mutation, Missense , Phenotype , Retinal Dystrophies/diagnostic imaging , Retinal Dystrophies/physiopathology , Retinitis Pigmentosa/genetics , Retrospective Studies , Visual AcuityABSTRACT
BACKGROUND: Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with two novel changes in ALMS1. CASE PRESENTATION: Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298 fs) and c.10769delC (p.T3590 fs) in ALMS1 gene were found. CONCLUSIONS: Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.
Subject(s)
Alstrom Syndrome/genetics , Cell Cycle Proteins/genetics , Mutation , Retinal Degeneration/etiology , Adult , Humans , Male , Siblings , Young AdultABSTRACT
Purpose: The purpose of this study was to analyze the natural history and phenotypic overlap of patients with microcephaly and a chorioretinopathy or familial exudative vitreoretinopathy (FEVR) ocular phenotype caused by mutations in KIF11, TUBGCP4, or TUBGCP6. Methods: Patients diagnosed with congenital microcephaly and chorioretinopathy or FEVR were included. Molecular investigations consisted of targeted genetic sequencing. Data from medical records, ophthalmologic examination and imaging, electroretinography, and visual fields were analyzed for systemic and ophthalmic features and evidence of posterior segment disease progression. Results: Twelve patients from 9 families were included and had a median of 8 years of follow-up. Nine patients had KIF11 variants, two had heterozygous TUBGCP6 variants, and one had heterozygous variants in TUBGCP4. All patients had reduced visual function and multiple individuals and families showed features of both chorioretinopathy and FEVR. Progression of posterior segment disease was highly variable, with some degree of increased atrophy of the macula or peripheral retina or increased vitreoretinal traction observed in 9 of 12 patients. Conclusions: Microcephaly due to mutations in KIF11, TUBGCP4, or TUBGCP6 can be associated with retinal disease on a spectrum from chorioretinal atrophy to FEVR-like posterior segment changes. Visually significant disease progression can occur and patients should be monitored closely by a team experienced in ophthalmic genetics.