Expansion Of Phenotypic Spectrum Research Articles

Sialidosis type II: Expansion of phenotypic spectrum and identification of a common mutation in seven patients

Sialidosis, an autosomal recessive disorder, is characterized by progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. It occurs as a result of biallelic mutations in the NEU1 gene. Sialidosis is traditionally classified as a milder, late-onset type I and a severe early-onset type II disease. The presence of a cherry-red spot is a well-established ophthalmological clue to the disorder. We present a clinical-radiological report of seven unrelated patients with molecularly confirmed sialidosis type II. To the best of our knowledge, This is the largest reported series of patients with Sialidosis type II. A novel, previously unreported ophthalmic phenotype of bulls-eye maculopathy, is described. All seven phenotypically heterogeneous patients had the same pathogenic variant (c.679G > A; p.Gly227Arg) at a homozygous level in the NEU1 gene. We propose that this is a common mutation in north Indians for this rare disorder. We also observed an overlap of symptoms and a continuum of phenotypes in type I and II Sialidosis.

Expansion of phenotypic spectrum of MYO15A pathogenic variants to include postlingual onset of progressive partial deafness

BackgroundMYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which ultimately requires cochlear implantation in early childhood. Recently, such variants have also been shown to possibly cause moderate-to-severe hearing loss. Herein, we also demonstrate that some MYO15A mutant alleles can cause postlingual onset of progressive partial deafness.MethodsTwo multiplex Korean families (SB246 and SB224), manifesting postlingual, progressive, partial deafness in an autosomal recessive fashion, were recruited. Molecular genetics testing was performed in two different pipelines, in a parallel fashion, for the SB246 family: targeted exome sequencing (TES) of 129 known deafness genes from the proband and whole exome sequencing (WES) of all affected subjects. Only the former pipeline was performed for the SB224 family. Rigorous bioinformatics analyses encompassing structural variations were executed to investigate any causative variants.ResultsIn the SB246 family, two different molecular diagnostic pipelines provided exactly the same candidate variants: c.5504G > A (p.R1835H) in the motor domain and c.10245_10247delCTC (p.S3417del) in the FERM domain of MYO15A. In the SB224 family, c.9790C > T (p.Q3264X) and c.10263C > G (p.I3421M) in the FERM domain were detected as candidate variants.ConclusionsSome recessive MYO15A variants can cause postlingual onset of progressive partial deafness. The phenotypic spectrum of DFNB3 should be extended to include such partial deafness. The mechanism for a milder phenotype could be due to the milder pathogenic potential from hypomorphic alleles of MYO15A or the presence of modifier genes. This merits further investigation.

Identification of 12 adaptor protein-2 sigma 2 subunit mutations in familial hypocalciuric hypercalcaemia type 3 and expansion of phenotypic spectrum.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Bladder exstrophy and extreme genital anomaly in a patient with pure terminal 1q deletion: Expansion of phenotypic spectrum

We describe a 5 2/12 years old male patient with a de novo deletion 1q43q44 of approximately 10.4 Mb in size. The boy presented with the classic features of chromosome 1q43q44 deletion syndrome including growth and psychomotor retardation, microcephaly, distinct facial features and various midline defects as agenesis of corpus callosum, cardiac and urogenital anomalies. Fronto-parietal simplified gyral pattern was an additional neuroimaging finding. The urogenital anomalies in our patient were remarkable in form of bladder exstrophy and severe hypogenitalism with a marked hypoplastic scrotum, small sized retractile testis and absent phallus. To the best of our knowledge, bladder exstrophy and absence phallus have not been previously reported in terminal deletion 1q43q44 syndrome. This report provides further evidence of phenotype–genotype correlation and expands the phenotypic spectrum of midline defects described with this syndrome.