26775
2022
eng
785–803
3-4
141
article
1
--
--
--
Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment
Usher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf-blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15%) probands displayed other genetic entities with dual sensory impairment, including Alström syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf-blind cohort was 92%. Two (3%) probands were partially solved and only 3 (5%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities.
Human Genetics
1432-1203
10.1007/s00439-021-02303-1
34148116
urn:nbn:de:bvb:20-opus-267750
publish
Human Genetics 2022, 141(3-4):785–803. DOI: 10.1007/s00439-021-02303-1
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Paulina Bahena
Narsis Daftarian
Reza Maroofian
Paola Linares
Daniel Villalobos
Mehraban Mirrahimi
Aboulfazl Rad
Julia Doll
Michaela A. H. Hofrichter
Asuman Koparir
Tabea Röder
Seungbin Han
Hamideh Sabbaghi
Hamid Ahmadieh
Hassan Behboudi
Cristina Villanueva-Mendoza
Vianney Cortés-Gonzalez
Rocio Zamora-Ortiz
Susanne Kohl
Laura Kuehlewein
Hossein Darvish
Elham Alehabib
Maria de Luz La Arenas-Sordo
Fatemeh Suri
Barbara Vona
Thomas Haaf
eng
uncontrolled
Usher syndrome
eng
uncontrolled
hearing impairment
eng
uncontrolled
combined retinal dystrophy
Medizin und Gesundheit
open_access
Institut für Humangenetik
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26775/Bahena_Human.pdf
17575
2018
eng
81
19
article
1
2019-01-31
--
--
The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family
Background:
Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.
Methods:
Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.
Results:
The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.
Conclusion:
In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.
BMC Medical Genetics
10.1186/s12881-018-0598-5
urn:nbn:de:bvb:20-opus-175755
BMC Medical Genetics (2018) 19:81. DOI: 10.1186/s12881-018-0598-5
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Michaela A. H. Hofrichter
Majid Mojarad
Julia Doll
Clemens Grimm
Atiye Eslahi
Neda Sadat Hosseini
Mohsen Rajati
Tobias Müller
Marcus Dittrich
Reza Maroofian
Thomas Haaf
Barbara Vona
eng
uncontrolled
3D modeling
eng
uncontrolled
autosomal recessive non-synstromic hearing loss
eng
uncontrolled
DFNB68
eng
uncontrolled
mixed hearing loss
eng
uncontrolled
whole exome sequencing
eng
uncontrolled
S1PR2
Medizin und Gesundheit
open_access
Institut für Humangenetik
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17575/Hofrichter_BMC_Medical_Genetics.pdf
20042
2019
eng
83
12
article
1
2020-03-04
--
--
Unbalanced segregation of a paternal t(9;11)(p24.3;p15.4) translocation causing familial Beckwith-Wiedemann syndrome: a case report
Background
The vast majority of cases with Beckwith-Wiedemann syndrome (BWS) are caused by a molecular defect in the imprinted chromosome region 11p15.5. The underlying mechanisms include epimutations, uniparental disomy, copy number variations, and structural rearrangements. In addition, maternal loss-of-function mutations in CDKN1C are found. Despite growing knowledge on BWS pathogenesis, up to 20% of patients with BWS phenotype remain without molecular diagnosis.
Case presentation
Herein, we report an Iranian family with two females affected with BWS in different generations. Bisulfite pyrosequencing revealed hypermethylation of the H19/IGF2: intergenic differentially methylated region (IG DMR), also known as imprinting center 1 (IC1) and hypomethylation of the KCNQ1OT1: transcriptional start site (TSS) DMR (IC2). Array CGH demonstrated an 8 Mb duplication on chromosome 11p15.5p15.4 (205,827-8,150,933) and a 1 Mb deletion on chromosome 9p24.3 (209,020-1,288,114). Chromosome painting revealed that this duplication-deficiency in both patients is due to unbalanced segregation of a paternal reciprocal t(9;11)(p24.3;p15.4) translocation.
Conclusions
This is the first report of a paternally inherited unbalanced translocation between the chromosome 9 and 11 short arms underlying familial BWS. Copy number variations involving the 11p15.5 region are detected by the consensus diagnostic algorithm. However, in complex cases which do not only affect the BWS region itself, characterization of submicroscopic chromosome rearrangements can assist to estimate the recurrence risk and possible phenotypic outcomes.
BMC Medical Genomics
10.1186/s12920-019-0539-y
urn:nbn:de:bvb:20-opus-200422
BMC Medical Genomics (2019) 12:83 https://doi.org/10.1186/s12920-019-0539-y
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Caroline Lekszas
Indrajit Nanda
Barbara Vona
Julia Böck
Farah Ashrafzadeh
Nahid Donyadideh
Farnoosh Ebrahimzadeh
Najmeh Ahangari
Reza Maroofian
Ehsan Ghayoor Karimiani
Thomas Haaf
eng
uncontrolled
Familial Beckwith-Wiedemann syndrome
eng
uncontrolled
copy number variation
eng
uncontrolled
duplication-deficiency
eng
uncontrolled
genomic imprinting
eng
uncontrolled
submicroscopic chromosome rearrangement
eng
uncontrolled
reciprocal translocation
Medizin und Gesundheit
open_access
Institut für Humangenetik
Förderzeitraum 2019
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20042/CarolineLekszas_BMCCMedicalGenomics_2019.pdf
26774
2021
eng
915–931
6
140
article
1
--
--
--
A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans
Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
Human Genetics
1432-1203
10.1007/s00439-020-02254-z
33496845
urn:nbn:de:bvb:20-opus-267740
publish
Human Genetics 2021, 140(6):915–931. DOI: 10.1007/s00439-020-02254-z
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Barbara Vona
Neda Mazaheri
Sheng-Jia Lin
Lucy A. Dunbar
Reza Maroofian
Hela Azaiez
Kevin T. Booth
Sandrine Vitry
Aboulfazl Rad
Franz Rüschendorf
Pratishtha Varshney
Ben Fowler
Christian Beetz
Kumar N. Alagramam
David Murphy
Gholamreza Shariati
Alireza Sedaghat
Henry Houlden
Cassidy Petree
Shruthi VijayKumar
Richard J. H. Smith
Thomas Haaf
Aziz El-Amraoui
Michael R. Bowl
Gaurav K. Varshney
Hamid Galehdari
eng
uncontrolled
deafness
eng
uncontrolled
CLRN2
eng
uncontrolled
gene
Medizin und Gesundheit
open_access
Institut für Humangenetik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26774/Vona_Human.pdf
17662
2018
eng
196
19
article
1
2019-02-14
--
--
Expanding the clinical phenotype of IARS2-related mitochondrial disease
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.
BMC Medical Genetics
10.1186/s12881-018-0709-3
urn:nbn:de:bvb:20-opus-176620
BMC Medical Genetics (2018) 19:196. DOI: 10.1186/s12881-018-0709-3
716344
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Barbara Vona
Reza Maroofian
Emanuele Bellacchio
Maryam Najafi
Kyle Thompson
Ahmad Alahmad
Langping He
Najmeh Ahangari
Abolfazl Rad
Sima Shahrokhzadeh
Paulina Bahena
Falk Mittag
Frank Traub
Jebrail Movaffagh
Nafise Amiri
Mohammad Doosti
Reza Boostani
Ebrahim Shirzadeh
Thomas Haaf
Daria Diodato
Miriam Schmidts
Robert W. Taylor
Ehsan Ghayoor Karimiani
eng
uncontrolled
adrenal insufficiency
eng
uncontrolled
CAGSSS
eng
uncontrolled
cataracts
eng
uncontrolled
growth hormone deficiency
eng
uncontrolled
IARS2
eng
uncontrolled
sensory neuropathy
eng
uncontrolled
sensorineural hearing loss
eng
uncontrolled
type II esophageal achalasia
eng
uncontrolled
skeletal dysplasia
Medizin und Gesundheit
open_access
Institut für Humangenetik
OpenAIRE
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17662/Vona_BMC_Medical_Genetics.pdf