DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) has been considered a prototypical mitochondriopathy and a textbook example for maternal inheritance linked to certain disease-causing variants in the mitochondrial genome. Recently, an autosomal recessive form of LHON (arLHON) has been described, caused by disease-causing variants in the nuclear encoded gene DNAJC30. METHODS AND RESULTS: In this study, we screened the DNAJC30 gene in a large Central European cohort of patients with a clinical diagnosis of LHON or other autosomal inherited optic atrophies (OA). We identified likely pathogenic variants in 35/1202 patients, corresponding to a detection rate of 2.9%. The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect. Furthermore, we identified two novel pathogenic variants in DNAJC30: the nonsense variant c.610G>T;p.(Glu204*) and the in-frame deletion c.230_232del;p.(His77del). Clinical investigation of the patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared with LHON associated with disease-causing variants in the mitochondrial DNA. CONCLUSION: This study expands previous findings on arLHON and emphasises the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients.

Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing.

Grange syndrome is an autosomal recessive condition characterized by arterial occlusions and hypertension. Syndactyly, brachydactyly, bone fragility, heart defects, and learning disabilities have also been reported. Loss-of-function variants in YY1AP1 have only recently been associated with Grange syndrome. YY1AP1 encodes for the transcription coactivator yin yang 1-associated protein 1 which regulates smooth muscle cell proliferation and differentiation. We here report on three siblings with steno-occlusive arterial disorder and syndactyly in two of them. Whole exome sequencing including near-splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing. Sanger sequencing demonstrated compound-heterozygosity in all affected siblings. RT-PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other. This is the first report of biallelic YY1AP1 variants in noncoding regions and just the second family with multiple affected siblings. Therefore, our report further delineates the phenotypic spectrum of Grange syndrome.

Molecular karyotyping as a relevant diagnostic tool in children with growth retardation with Silver-Russell features.

OBJECTIVE: To determine the contribution of submicroscopic chromosomal imbalances to the etiology of Silver-Russell syndrome (SRS) and SRS-like phenotypes. STUDY DESIGN: We performed molecular karyotyping in 41 patients with SRS or SRS-like features without known chromosome 7 and 11 defects using the Affymetrix SNP Array 6.0 system (Affymetrix, High Wycombe, United Kingdom). RESULTS: In 8 patients, pathogenic copy number variations with sizes ranging from 672 kb to 9.158 Mb were identified. The deletions in 1q21, 15q26, 17p13, and 22q11 were associated with known microdeletion syndromes with overlapping features with SRS. The duplications in 22q13 and Xq25q27 represent unique novel copy number variations but have an obvious influence on the phenotype. In 5 additional patients, the pathogenetic relevance of the detected variants remained unclear. CONCLUSION: Pathogenic submicroscopic imbalances were detectable in a significant proportion of patients with short stature and features reminiscent of SRS. Therefore, molecular karyotyping should be implemented in routine diagnostics for growth-retarded patients with even slight dysmorphisms suggestive for SRS.

New mutations in the ATM gene and clinical data of 25 AT patients.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

Community acquired Staphylococcus aureus meningitis and cerebral abscesses in a patient with a hyper-IgE and a Dubowitz-like syndrome.

The Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency which recently has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3). Although HIES is characterized by recurrent staphylococcal infections, the microbial invasion of the central nervous system (CNS) is definitively uncommon. We here report on Staphylococcus aureus meningitis and cerebral abscesses acquired in the community in a 31-year-old female patient with a de novo heterozygous mutation of STAT3 and a Dubowitz-like syndrome characterized by growth retardation, microcephaly and eczema. The patient presented with a relative paucity of clinical symptoms despite severe cerebrospinal fluid pathology and multiple cerebral abscesses. Antimicrobial as well as treatment with intravenous immunoglobulin was well tolerated and led to a slow recovery over a 6 months period. Our observation adds community acquired S. aureus meningitis to the list of life-threatening infections in STAT3-deficient HIES and should also raise awareness for the unusual clinical presentation of severe neuroinfection in this syndrome. Whether the association of HIES with Dubowitz-like syndrome was purely coincidental, possibly supportive of the CNS infection, or suggests a genetic overlap of these syndromes, awaits clarification.