TY  - JOUR
A1  - Vona, Barbara
A1  - Hofrichter, Michaela A. H.
A1  - Schröder, Jörg
A1  - Shehata-Dieler, Wafaa
A1  - Nanda, Indrajit
A1  - Haaf, Thomas
T1  - Hereditary hearing loss SNP-microarray pilot study
JF  - BMC Research Notes
N2  - Objectives:
Despite recent advancements in diagnostic tools, the genomic landscape of hereditary hearing loss remains largely uncharacterized. One strategy to understand genome-wide aberrations includes the analysis of copy number variation that can be mapped using SNP-microarray technology. A growing collection of literature has begun to uncover the importance of copy number variation in hereditary hearing loss. This pilot study underpins a larger effort that involves the stage-wise analysis of hearing loss patients, many of whom have advanced to high-throughput sequencing analysis.

Data description:
Our data originate from the Infinium HumanOmni1-Quad v1.0 SNP-microarrays (Illumina) that provide useful markers for genome-wide association studies and copy number variation analysis. This dataset comprises a cohort of 108 individuals (99 with hearing loss, 9 normal hearing family members) for the purpose of understanding the genetic contribution of copy number variations to hereditary hearing loss. These anonymized SNP-microarray data have been uploaded to the NCBI Gene Expression Omnibus and are intended to benefit other investigators interested in aggregating platform-matched array patient datasets or as part of a supporting reference tool for other laboratories to better understand recurring copy number variations in other genetic disorders.
KW  - copy number variation
KW  - genotyping arrays
KW  - hereditary hearing loss
KW  - illumina
KW  - infinium HumanOmni1-Quad
KW  - SNP-microarray
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176239
VL  - 11
IS  - 391
ER  - 
TY  - JOUR
A1  - Vona, Barbara
A1  - Maroofian, Reza
A1  - Bellacchio, Emanuele
A1  - Najafi, Maryam
A1  - Thompson, Kyle
A1  - Alahmad, Ahmad
A1  - He, Langping
A1  - Ahangari, Najmeh
A1  - Rad, Abolfazl
A1  - Shahrokhzadeh, Sima
A1  - Bahena, Paulina
A1  - Mittag, Falk
A1  - Traub, Frank
A1  - Movaffagh, Jebrail
A1  - Amiri, Nafise
A1  - Doosti, Mohammad
A1  - Boostani, Reza
A1  - Shirzadeh, Ebrahim
A1  - Haaf, Thomas
A1  - Diodato, Daria
A1  - Schmidts, Miriam
A1  - Taylor, Robert W.
A1  - Karimiani, Ehsan Ghayoor
T1  - Expanding the clinical phenotype of IARS2-related mitochondrial disease
JF  - BMC Medical Genetics
N2  - Background:
IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies.

Methods:
Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis.

Results:
Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein.

Conclusions:
This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.
KW  - adrenal insufficiency
KW  - CAGSSS
KW  - cataracts
KW  - growth hormone deficiency
KW  - IARS2
KW  - sensory neuropathy
KW  - sensorineural hearing loss
KW  - type II esophageal achalasia
KW  - skeletal dysplasia
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176620
VL  - 19
IS  - 196
ER  -