The NBN founder mutation-Evidence for a country specific difference in age at cancer manifestation.

Background: Nijmegen breakage syndrome (NBS) is an autosomal-recessive chromosome instability disorder characterized by, among others, hypersensitivity to X-irradiation and an exceptionally high risk for lymphoid malignancy. The vast majority of NBS patients is homozygous for a common Slavic founder mutation, c.657del5, of the NBN gene, which is involved in the repair of DNA double-strand breaks (DSBs).

Telomere attrition and dysfunction: a potential trigger of the progeroid phenotype in nijmegen breakage syndrome.

Background: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy.

Results: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL.

The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation.

Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals.

DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects.

Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified.

Long term follow-up in a patient with a de novo microdeletion of 14q11.2 involving CHD8.

We identified a de novo deletion of 14q11.2 in a Czech patient with developmental delay, mild autistic features, macrosomy, macrocephaly, orthognathic deformities, and dysmorphic facial features. The clinical follow-up of the patient lasting 14 years documented changes in the facial dysmorphism from infancy to adolescence.

[Mutagenic effect of advanced paternal age in neurocardiofaciocutaneous syndrome].

Background: Increased frequency of chromosomal aberration in children of mothers aged 35 years and older is very well known and since 1973 it is an indication to investigate the foetal karyotype in cells obtained by invasive method (amniocentesis), because the genetic risk of severe affection is higher than the risk of necessary invasive method. Mutagenic effect of advanced paternal age is known only among geneticists (1-4). The reason is not only low absolute risk of new mutation but particularly a high number of involved genes and last not least the limited spectrum of autosomal dominant disorders without abiotrofic character.

Deletions in the 3' part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome.

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals.

An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome.

The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype.

A mutation in the c-fos gene associated with congenital generalized lipodystrophy.

Background: Congenital generalized lipodystrophy (CGL) or Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare genetic syndrome characterized by the absence of adipose tissue. As CGL is thought to be related to malfunctions in adipocyte development, genes involved in the mechanisms of adipocyte biology and maintenance or differentiation of adipocytes, especially transcription factors are candidates. Several genes (BSCL1-4) were found to be associated to the syndrome but not all CGL patients carry mutations in these genes.

Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome.

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families.

Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies.

Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS.

Characterisation of ATM mutations in Slavic Ataxia telangiectasia patients.

Ataxia telangiectasia (AT) is a genomic instability syndrome characterised, among others, by progressive cerebellar degeneration, oculocutaneous telangiectases, immunodeficiency, elevated serum alpha-phetoprotein level, chromosomal breakage, hypersensitivity to ionising radiation and increased cancer risk. This autosomal recessive disorder is caused by mutations in the ataxia telangiectasia mutated (ATM) gene coding for serine/threonine protein kinase with a crucial role in response to DNA double-strand breaks. We characterised genotype and phenotype of 12 Slavic AT patients from 11 families.

[Heterozygous carriers of Slavic mutation 657del5 of NBN gene in patients with colorectal cancer].

Background: Nijmegen breakage syndrome (NBS) is one of the chromosomal instability syndromes due to DNA repair disorder. The syndrome is autosomal recessive determined, in homozygotes is characterized by many disorders including high predisposition to lymphoreticular malignancy in childhood and adolescence.

Methods: Laboratory findings represent low level of immunoglobulins, B and T lymphocytes, increased sensitivity to the mutagens, especially hyperradiosensitivity and increased chromosomal instability.

A restricted spectrum of NRAS mutations causes Noonan syndrome.

Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway. Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder. These findings provide evidence for an obligate dependency on proper NRAS function in human development and growth.

Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome.

Patients affected by the autosomal recessive Nijmegen Breakage Syndrome (NBS [MIM 251260]) have possibly the highest risk for developing a malignancy of all the chromosomal instability syndromes. This reflects the profound disturbance to genomic integrity and cellular homeostasis that is caused by the mutation of the essential mammalian gene, NBN. Whilst null-mutation of Nbn is lethal in the mouse, NBS patients survive due to the fact that the common human founder mutation, found in over 90% of patients, is in fact hypomorphic and leads, by alternative translation, to varying amounts of a partially functional carboxy-terminal protein fragment, p70-nibrin.

Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence.

Noonan syndrome (NS) and related disorders are caused by mutations in various genes encoding molecules involved in the RAS-MAPK signalling cascade. There are strong genotype-phenotype correlations. BRAF is the major gene for cardio-facio-cutaneous syndrome (CFCS), and usually patients with a BRAF mutation have significant cognitive impairment.

Goltz-Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap.

Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases.

Polycystic kidney and hepatic disease with mental retardation and hand anomalies in three siblings.

A family with three children affected with congenital polycystic kidneys, hepatic fibrosis, mental retardation, minor anomalies of the hands, and dysmorphic facial features is reported. All children progressed to chronic renal failure. Linkage to the locus for autosomal recessive polycystic kidney disease was excluded by haplotype analysis.

Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type.

Objective: To delineate a new syndrome of brain dysgenesis and cutis laxa based on the description of 11 patients belonging to nine unrelated families recruited through an international collaboration effort.

Methods: Careful clinical assessment of patients from birth to the age of 23 years with follow-up studies ranging from 3 to 20 years. Biochemical studies of serum proteins glycosylation by isoelectric focusing and capillary zone electrophoresis were performed in 10 patients.

Two independent chromosomal rearrangements, a very small (550 kb) duplication of the 7q subtelomeric region and an atypical 17q11.2 (NF1) microdeletion, in a girl with neurofibromatosis.

Most patients with neurofibromatosis (NF1) are endowed with heterozygous mutations in the NF1 gene. Approximately 5% show an interstitial deletion of chromosome 17q11.2 (including NF1) and in most cases also a more severe phenotype.

Cancer risk of heterozygotes with the NBN founder mutation.

Background: The autosomal recessive chromosomal instability disorder Nijmegen breakage syndrome (NBS) is associated with increased risk of lymphoid malignancies and other cancers. Cells from NBS patients contain many double-stranded DNA breaks. More than 90% of NBS patients are homozygous for a founder mutation, 657del5, in the NBN gene.

Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome.

Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS.