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 .

Methods And Results: In this study, we screened the gene in a large Central European cohort of patients with a clinical diagnosis of LHON or other autosomal inherited optic atrophies (OA).

One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver-Russell syndrome.

Background: Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported.

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome.

AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides.

Uncovering frequent motives of action by which variants impair 3' splice site (3'ss) recognition and selection is essential to improve our understanding of this complex process. Through several mini-gene experiments, we demonstrate that the pyrimidine (Y) to purine (R) transversion NM_000267.3(NF1):c.

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.

Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification.

In this paper, we report three patients with severe palmoplantar keratoderma associated with ichthyosis and sensorineural deafness. Biallelic mutations were found in VPS33B, encoding VPS33B, a Sec1/Munc18 family protein that interacts with Rab11a and Rab25 proteins and is involved in trafficking of the collagen-modifying enzyme LH3. Two patients were homozygous for the missense variant p.

Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears.

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch.

Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome.

Background: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, β 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development.

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).

Mutations in MECP2 exon 1 in classical Rett patients disrupt MECP2_e1 transcription, but not transcription of MECP2_e2.

The overwhelming majority of Rett syndrome cases are caused by mutations in the gene MECP2. MECP2 has two isoforms, termed MECP2_e1 and MECP2_e2, which differ in their N-terminal amino acid sequences. A growing body of evidence has indicated that MECP2_e1 may be the etiologically relevant isoform in Rett Syndrome based on its expression profile in the brain and because, strikingly, no mutations have been discovered that affect MECP2_e2 exclusively.

CLMP is required for intestinal development, and loss-of-function mutations cause congenital short-bowel syndrome.

Background & Aims: Short-bowel syndrome usually results from surgical resection of the small intestine for diseases such as intestinal atresias, volvulus, and necrotizing enterocolitis. Patients with congenital short-bowel syndrome (CSBS) are born with a substantial shortening of the small intestine, to a mean length of 50 cm, compared with a normal length at birth of 190-280 cm. They also are born with intestinal malrotation.

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.

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.

Metopic and sagittal synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations or complete deletions of GLI3.

Greig cephalopolysyndactyly syndrome (GCPS) is a multiple congenital malformation characterised by limb and craniofacial anomalies, caused by heterozygous mutation or deletion of GLI3. We report four boys and a girl who were presented with trigonocephaly due to metopic synostosis, in association with pre- and post-axial polydactyly and cutaneous syndactyly of hands and feet. Two cases had additional sagittal synostosis.

Translocation and deletion around SOX9 in a patient with acampomelic campomelic dysplasia and sex reversal.

Campomelic dysplasia (MIM 114290) is a severe malformation syndrome frequently accompanied by male-to-female sex reversal. Causative are mutations within the SOX9 gene on 17q24.3 as well as chromosomal aberrations (translocations, inversions or deletions) in the vicinity of SOX9.

Predictive diagnosis of the cancer prone Li-Fraumeni syndrome by accident: new challenges through whole genome array testing.

Background: Li-Fraumeni syndrome greatly increases the risk of developing several types of cancer and is usually caused by TP53 germline mutations. Predictive testing of at-risk family members is only offered after a complex genetic counselling process. Recently the clinical implementation of array comparative genomic hybridisation (CGH) has revolutionised the diagnosis of patients with syndromic or non-syndromic mental retardation and has evolved to a routinely performed high resolution whole genome scan.

Characterization of a de novo translocation t(5;18)(q33.1;q12.1) in an autistic boy identifies a breakpoint close to SH3TC2, ADRB2, and HTR4 on 5q, and within the desmocollin gene cluster on 18q.

We have recently reported the identification of a de novo balanced translocation t(5;18)(q33.1;q12.1) in a boy with autism.

Mental retardation in a girl with a subtelomeric deletion on chromosome 20q and complete deletion of the myelin transcription factor 1 gene (MYT1).

A great number of syndromes and inborn errors of metabolism associated with impaired development have been observed, but the aetiology of mental retardation remains unclear in a considerable proportion of cases. Here, we present the clinical and molecular data from a patient with a new de novo subtelomeric deletion on chromosome 20 [46,XX.ish del(20)(qter-)].

Distal monosomy 16p13.3/distal trisomy 2p24.2-pter: molecular-cytogenetic characterisation and phenotype.

We describe a 4-year-old boy with various facial dysmorphic features such as downslanting palpebral fissures, ptosis, hypertelorism, broad nasal bridge, small and low-set ears, broad philtrum, and micrognathia. In addition, profound mental retardation, myopia, muscular hypotonia as well as genital and cardiovascular abnormalities are also present. Refinement of the breakpoints by cytogenetic techniques, in particular the increase of banding resolution in conventional cytogenetic analysis, has enabled the correct diagnosis, as proven by fluorescence in situ hybridisation (FISH) using whole chromosome painting and single copy probes.