TY  - JOUR
A1  - Hofrichter, Michaela A. H.
A1  - Doll, Julia
A1  - Habibi, Haleh
A1  - Enayati, Samaneh
A1  - Mehrjardi, Mohammad Yahya Vahidi
A1  - Müller, Tobias
A1  - Dittrich, Marcus
A1  - Haaf, Thomas
A1  - Vona, Barbara
T1  - Exome-wide copy number variation analysis identifies a COL9A1 in frame deletion that is associated with hearing loss
JF  - European Journal of Medical Genetics
N2  - Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome (STL) present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exons 6 to 33 of COL9A1 was detected via exome-based copy number variation analysis. The deleted exons were confirmed by PCR in the patient and his affected brother, who both have non-syndromic HL. Segregation analysis via qPCR confirmed the parents as heterozygous deletion carriers. Breakpoint analysis mapped the homozygous deletion spanning introns 5 to 33 (g.70,948,188_70,997,277del, NM_001851.4(COL9A1):c.697–3754_2112+769del, p.(Phe233_Ser704del), with an additional 67 bp of inserted intronic sequence that may have originated due to a fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) mechanism. This mechanism has not been previously implicated in HL or STL. This is also the first reported copy number variation in COL9A1 that was identified through an exome data set in an Iranian family with apparent non-syndromic HL. The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL.
KW  - COL9A1
KW  - copy number variation
KW  - FoSTeS/MMBIR mechanism
KW  - non-syndromic hearing loss
KW  - Stickler syndrome
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322008
VL  - 62
ER  - 
TY  - JOUR
A1  - Lekszas, Caroline
A1  - Nanda, Indrajit
A1  - Vona, Barbara
A1  - Böck, Julia
A1  - Ashrafzadeh, Farah
A1  - Donyadideh, Nahid
A1  - Ebrahimzadeh, Farnoosh
A1  - Ahangari, Najmeh
A1  - Maroofian, Reza
A1  - Karimiani, Ehsan Ghayoor
A1  - Haaf, Thomas
T1  - Unbalanced segregation of a paternal t(9;11)(p24.3;p15.4) translocation causing familial Beckwith-Wiedemann syndrome: a case report
JF  - BMC Medical Genomics
N2  - 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.
KW  - Familial Beckwith-Wiedemann syndrome
KW  - copy number variation
KW  - duplication-deficiency
KW  - genomic imprinting
KW  - submicroscopic chromosome rearrangement
KW  - reciprocal translocation
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200422
VL  - 12
ER  -