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PubMedDate not supplied

Shprintzen (velo-cardio-facial) syndrome: a rare case.

Shprintzen syndrome (velo-cardio-facial, VCFS) is a very rare morbid entity, seen in either familial or sporadic forms, with major clinical findings such as facial dysmorphism, cleft palate, cardiovascular (especially conotruncal-anomalies), mild/moderate mental retardation, or, more commonly, observed learning difficulty. Tendency to behavioral disorders and bipolar schizophrenic diseases may be present in these cases. Autosomal dominant inheritance has been reported. VCFS appears as a consequence of microdeletion in the 22q11 chromosomal band. Although each syndrome has different clinical reflections, genetically the defect is located on the same chromosome.A 4-year-old boy was admitted to our clinic with a syndromic face and the diagnosis of tetralogy of Fallot. The patient underwent total correction of the cardiac defect. Atypical facial appearance, cleft palate, and malformed hand-fingers were present. With the aid of pediatric and genetic consultation (fluorescence in situ hybridization test), Shprintzen syndrome was confirmed. Both early and late postoperative periods of the patient were uneventful. The patient was closely consulted by a specialist psychologist during and after the hospitalization period. These children can be integrated into social life earlier through early surgical intervention for cardiac defects and facial deformations as well as neurologic and/or neuropsychiatric evaluation.

Abnormalities, Multiple↗
PubMed2005

A novel frame shift mutation in the HMG box of the SRY gene in a patient with complete 46,XY pure gonadal dysgenesis.

Pure gonadal dysgenesis or Swyer syndrome is a sex-reversal disorder resulting from embryonic testicular regression sequences especially during the first few weeks of fetal life and is induced by mutations in the SRY gene. In the present report, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis. Molecular analysis using sequential PCR to detect Y chromosomal microdeletions showed the presence of SRY, ZFY and AZFa, b and c regions. Automated sequencing of the SRY region revealed a new mutation (deletion of A (adenine) in codon 82 at position +244), leading to a frame shift mutation within the helix I of the HMG-box domain. This mutation generates a truncated protein and is very likely to produce an impairment of SRY DNA binding activity. The present findings further support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.

Adolescent↗
PubMed2005

Inactivation of TGFbeta signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome.

Specific inactivation of TGFbeta signaling in neural crest stem cells (NCSCs) results in cardiovascular defects and thymic, parathyroid, and craniofacial anomalies. All these malformations characterize DiGeorge syndrome, the most common microdeletion syndrome in humans. Consistent with a role of TGFbeta in promoting non-neural lineages in NCSCs, mutant neural crest cells migrate into the pharyngeal apparatus but are unable to acquire non-neural cell fates. Moreover, in neural crest cells, TGFbeta signaling is both sufficient and required for phosphorylation of CrkL, a signal adaptor protein implicated in the development of DiGeorge syndrome. Thus, TGFbeta signal modulation in neural crest differentiation might play a crucial role in the etiology of DiGeorge syndrome.

Adaptor Proteins, Signal Transducing↗
PubMed1997

A region of mouse chromosome 16 is syntenic to the DiGeorge, velocardiofacial syndrome minimal critical region.

DGS and VCFS, haploinsufficiencies characterized by multiple craniofacial and cardiac abnormalities, are associated with a microdeletion of chromosome 22q11.2. Here we document synteny between a 150-kb region on mouse chromosome 16 and the most commonly deleted portion of 22q11.2. Seven genes, all of which are transcribed in the early mouse embryo, have been identified. Of particular interest are two serine/threonine kinase genes and a novel goosecoid-like homeobox gene (Gscl). Comparative sequence analysis of a 38-kb segment reveals similarities in gene content, order, exon composition, and transcriptional direction. Therefore, if deletion of these genes results in DGS/VCFS in humans, then haploinsufficiencies involving this region of chromosome 16 should recapitulate the developmental field defects characteristic of this syndrome.

Abnormalities, Multiple↗
PubMed2004

Comparison of TFII-I gene family members deleted in Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a neurological disorder resulting from a microdeletion, typically 1.5 megabases in size, at 7q11.23. Atypical patients implicate genes at the telomeric end of this multigene deletion as the main candidates for the pathology of WBS in particular the unequal cognitive profile associated with the condition. We recently identified a gene (GTF2IRD2) that shares homology with other members of a unique family of transcription factors (TFII-I family), which reside in the critical telomeric region. Using bioinformatics tools this study focuses on the detailed assessment of this gene family, concentrating on their characteristic structural components such as the leucine zipper (LZ) and I-repeat elements, in an attempt to identify features that could aid functional predictions. Phylogenetic analysis identified distinct I-repeat clades shared between family members. Linking functional data to one such clade has implicated them in DNA binding. The identification of PEST, synergy control motifs, and sumoylation sites common to all family members suggest a shared mechanism regulating the stability and transcriptional activity of these factors. In addition, the identification/isolation of short truncated isoforms for each TFII-I family member implies a mode of self-regulation. The exceptionally high identity shared between GTF2I and GTF2IRD2, suggests that heterodimers as well as homodimers are possible, and indicates overlapping functions between their respective short isoforms. Such cross-reactivity between GTF2I and GTF2IRD2 short isoforms might have been the evolutionary driving force for the 7q11.23 chromosomal rearrangement not present in the syntenic region in mice.

Amino Acid Motifs↗
PubMed2026

Elucidating the Role of SET as a Key Contributor to Neurodevelopmental Disability Within the 9q34.11 Deletion Syndrome Interval.

The 9q34.11 chromosomal region contains multiple neurodevelopmental genes involved in synaptic transmission, axonal structure and neuronal maturation. Pathogenic microdeletions, duplications and single nucleotide variants in numerous genes were previously linked with neurodevelopmental disorders (NDDs). Amongst them, SET has recently been implicated in a rare NDD with speech delay and facial dysmorphism. This study reports a female with a heterozygous de novo deletion impacting SET but not other NDD-associated genes at 9q34.11. The proband was initially diagnosed with atypical Rett syndrome with overlapping clinical features of SET haploinsufficiency. The deletion was confirmed using microarray and long-read sequencing. Subsequent quantitative proteomic evaluation identified a significant decrease of SET protein in patient-derived fibroblasts compared to control lines. This study provides insights into the proband's clinical course over their 28 year diagnostic odyssey, and emphasises the benefits of early speech therapy interventions. The proband had no functional speech, but regained the capacity to meaningfully communicate and articulate a limited vocabulary in adulthood, concordant with other reported non-paediatric cases of SET-NDD. This study expands current knowledge on the genotypic and phenotypic spectra of SET-NDD, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.

Humans↗
PubMed2026

Clinical Variability and Genotype-Driven Outcomes in CHRND-Related Congenital Myasthenic Syndrome.

BACKGROUND: Congenital myasthenic syndromes (CMS) caused by pathogenic variants in CHRND, encoding the δ-subunit of the nicotinic acetylcholine receptor (AChR), are rare, and data on genotype-phenotype correlations and long-term outcomes are limited. METHODS: We performed a retrospective, multicenter study of nine patients with genetically confirmed CHRND-related CMS from specialized neuromuscular centers. Clinical, electrophysiological, genetic, and therapeutic data were systematically collected. All diagnoses were established by exome sequencing during routine clinical work-up. RESULTS: Eight patients were compound heterozygous and one was homozygous for pathogenic CHRND variants, including nonsense, missense, splice-site variants, and one microdeletion. Disease onset ranged from the neonatal period (n = 7) to adolescence (n = 2). Three patients were followed longitudinally for 22-43 years. Ocular involvement, particularly ptosis and ophthalmoparesis, was present in all patients. Generalized fatigable weakness was common, whereas bulbar and respiratory involvement occurred in a subset and reflected overall disease severity. Genotypes including a null allele or a homozygous missense variant tended to be associated with more severe phenotypes, while compound heterozygous missense variants were linked to a broader and generally milder spectrum, sometimes limited to ocular symptoms. Long-term outcomes ranged from minimal symptoms under therapy to severe motor impairment with respiratory insufficiency, highlighting substantial interindividual variability. CONCLUSIONS: This study expands the phenotypic and genotypic spectrum of CHRND-related CMS and underscores the critical role of genotype in determining disease severity. Comprehensive genetic testing, longitudinal phenotyping, and genotype-informed management are essential for optimal diagnosis and care in this rare disorder.

Humans↗
PubMed2004

Prader-Willi syndrome resulting from an unbalanced translocation: characterization by array comparative genomic hybridization.

Prader-Willi syndrome (PWS) is caused by lack of expression of paternally inherited genes on chromosome 15q11-->15q13. Most cases result from microdeletions in proximal chromosome 15q. The remainder results from maternal uniparental disomy of chromosome 15, imprinting center defects, and rarely from balanced or unbalanced chromosome rearrangements involving chromosome 15. We report a patient with multiple congenital anomalies, including craniofacial dysmorphology, microcephaly, bilateral cryptorchidism, and developmental delay. Cytogenetic analysis showed a de novo 45,XY,der(5)t(5;15)(p15.2;q13), -15 karyotype. In effect, the proband had monosomies of 5p15.2-->pter and 15pter-->15q13. Methylation polymerase chain reaction analysis of the promoter region of the SNRPN gene showed only the maternal allele, consistent with the PWS phenotype. The proband's expanded phenotype was similar to other patients who have PWS as a result of unbalanced translocations and likely reflects the contribution of the associated monosomy. Array comparative genomic hybridization (array CGH) confirmed deletions of both distal 5p and proximal 15q and provided more accurate information as to the size of the deletions and the molecular breakpoints. This case illustrates the utility of array CGH in characterizing complex constitutional structural chromosome abnormalities at the molecular level.

Chromosome Deletion↗
PubMed2003

Prenatal diagnosis for placental steroid salfatase deficiency with fluorescence in situ hybridization: a case of X-linked ichthyosis.

X-linked ichthyosis (XLI) is a relatively common genetic disorder that occurs in about one in every 2000-6000 male births. Clinically, XLI is characterized by a generalized scaling of the skin, with large, polygonal, dark brown scale, and more prominent on the extensor aspects of the limbs. It is known that an undetectable maternal serum, unconjugated estriol, associated with placental steroid sulfatase (STS) deficiency, may be the cause of cause of XLI. In most case, STS deficiency is caused by a complete or partial deletion of the STS gene mapped on chromosome Xp22.3. We describe here the prenatal detection of a male fetus affected with STS deficiency as a result of an undetectable unconjugated estriol in the second-trimester maternal serum screening. Microdeletion of the STS gene was confirmed by fluorescence in situ hybridization analysis of cultured amniotic fluid.

Adult↗
PubMed1996

Molecular genetic diagnosis of von Hippel-Lindau disease: analysis of five Japanese families.

We analyzed deoxyribonucleic acids from blood samples of five Japanese von Hippel-Lindau (VHL) disease families (three familial cases, two new mutations) for the presence of VHL gene mutations by single-strand conformational polymorphism analysis and direct sequencing. Four of the five families showed germ line mutations in VHL gene, comprising 2 missense mutations, 1 deletion, and 1 splice-site mutation. Two families had VHL gene mutations at exon 1; 1 family at exon 3; and 1 family at the splice-site adjacent to exon 3. Presymptomatic patients were accurately diagnosed by these methods. However, one family did not show a VHL gene mutation in the germ line but showed a somatic mutation at exon 2 in the hemangioblastoma tissue. The consequence of the somatic mutation was a microdeletion leading to a frameshift mutation. Our study is the first report of VHL gene analyses of Japanese VHL disease families, and suggests that not only germ line mutation, but also somatic mutation can lead to development of a tumor associated with the VHL disease.

Base Sequence↗
PubMed2006

Human alpha2-globin nonsense-mediated mRNA decay induced by a novel alpha-thalassaemia frameshift mutation at codon 22.

We describe a novel alpha-thalassaemia determinant in a 3-year-old girl presenting a mild microcytic and hypochromic anaemia, and normal haemoglobin A2 level. Molecular studies revealed heterozygosity for a novel microdeletion (-C) at codon 22 of the alpha2-globin gene. As the frameshift mutation generates a premature translation termination codon at position 48/49, we investigated the effect of the nonsense codon on the alpha2-globin gene expression. Although it does not affect RNA splicing, the premature nonsense codon induces accelerated mRNA degradation. To our knowledge, this is the first time the nonsense-mediated mRNA decay has been reported to occur in human alpha-globin mRNA.

Codon, Nonsense↗
PubMed1987

Deletion of the DXS165 locus in patients with classical choroideremia.

Using various probes from the Xq21 region which is known to carry the choroideremia (tapetochoroideal dystrophy, TCD) locus, we have screened the DNAs from eight unrelated male choroidermia patients for microdeletions. In two of these patients, but not in any of 45 males tested as controls, lack of hybridization signals with probe plbD5 suggested a deletion encompassing the DXS165 locus and (part of) the TCD gene. Absence of additional clinical features in these patients and the fact that two closely linked, and probably flanking, TCD markers (DXYS1 and DXS72) are not deleted may indicate that the physical distance between the DXS165 locus and the TCD gene is small.

Choroid↗
PubMed1994

Interstitial deletion of 22q11 in DiGeorge syndrome detected by high resolution and molecular analysis.

Two patients with DiGeorge syndrome (DGS), one with and one without characteristic dysmorphic facial features, were studied by high resolution banding, fluorescence in situ hybridization (FISH) and quantitative Southern blotting. In both patients, even in the one with no typical facial stigmata, a microdeletion within 22q11.2 was detected. FISH analysis, in particular, is most useful in screening for 22q11.2 segmental monosomy in patients with DGS and DGS-related features.

Blotting, Southern↗
PubMed1995

Clinical and molecular genetic findings in five patients with Miller-Dieker syndrome.

Five patients with type 1 lissencephaly, typical features of Miller-Dieker syndrome and apparently normal karyotypes were investigated for microdeletions in chromosome 17p13.3. Analysis of loci D17S5 and D17S379 by polymerase chain reaction and fluorescence in situ hybridization revealed a deletion in three cases. No deletion was observed in the remaining two cases. Given the almost identical clinical picture of the five patients, the great variation in the molecular findings argues against Miller-Dieker syndrome being a contiguous gene syndrome.

Abnormalities, Multiple↗
PubMed1996

Chromosome 22q11 deletion and other chromosome aberrations in cases with cleft palate, congenital heart defects and/or mental disability. A survey based on the Danish Facial Cleft Register.

Velo-cardio-facial syndrome (VCFS) is a syndrome associated with haplo-insufficiency of genes at chromosome 22q11. The syndrome has a broad phenotypic spectrum including multiple anomalies, of which cleft palate (CP), congenital heart defects (CHD), and mental disabilities are among the most common. Hence, a high prevalence of 22q11 deletions should be expected among cases with a combination of CP and CHD or/and mental disability. In Denmark a population-based database comprising 2301 CP cases born 1936-1987 has been established. Cases with CP and CHD or/and mental disabilities were selected from the register. By using public registers 39 living cases were identified, among whom 15 agreed to blood sampling and testing for 22q11 deletion using FISH (fluorescence in situ hybridization) analysis. Four deletion cases were identified. Using a polymorphic microsatellite marker (D22S264), two cases were shown to be de novo deletions of maternal origin. The parental origin in the two other cases could not be determined. The patients ranged in age from 7 to 40 years. All patients had mental impairment, and one also showed signs of paranoid psychosis. Two cases had CHD. Furthermore, five cases previously karyotyped had other chromosomal aberrations. The study shows that facial cleft registers are an obvious source for identifying a group of patients with a high risk of VCFS and chromosome 22q11 microdeletion. These individuals as well as their families can benefit from genetic counselling.

Abnormalities, Multiple↗
PubMed1997

Möbius-like syndrome associated with a 1;2 chromosome translocation.

We report here a rare case of Möbius-like syndrome associated with a 1;2 chromosome reciprocal translocation (46,XY,t(1;2)(p22.3;q21.1). The patient had facial diplegia, ptosis, anteverted nostrils, malformed and lowset ears, and slight developmental delay. Since a microdeletion could be present at the breakpoint in a reciprocal translocation, it is possible that the gene responsible for Möbius syndrome is located in this region of chromosome 1.

Chromosomes, Human, Pair 1↗
PubMed1998

Recent progress in the molecular genetics of congenital heart defects.

Congenital heart defects (CHD) constitute the single most common anatomic class of birth defects and are a major cause of infant mortality. Correlation of normal and pathological embryology/anatomy has led to the formulation of mechanistic models, but there is limited understanding of the genetic basis for the inferred embryological processes. Most evidence points to extensive etiologic heterogeneity and a re-evaluation of simple multifactorial models is required. The recent identification of several genes responsible for congenital heart defects in the context of more complex clinical disorders provides significant entry points for the genetic analysis of human heart development. The association of aneusomies (particularly microdeletion syndromes) with specific cardiac lesions provides further strong support for mechanistic classification. Studies in the mouse are laying the groundwork for a comprehensive genetic model of cardiac organogenesis. Nevertheless, the basis for the large majority of CHD, especially isolated defects, remains obscure. Dissection of the genetic components of CHD is one of the greatest challenges in medical genetics for the coming decades.

Animals↗
PubMed1998

A gene-dosage PCR method for the detection of elastin gene deletions in patients with Williams syndrome.

Williams syndrome (WS) is a multisystem developmental disorder associated with microdeletions at 7q11.23 that involve several genes, including the elastin gene. Using genomic DNA from a panel of normal individuals and WS patients with established hemizygosity of the elastin gene locus, we have developed a quantitative polymerase chain reaction (PCR)-based gene-dosage assay that rapidly detects the loss of one allele of the elastin gene. Using this procedure, we also studied a family in which the proband was previously diagnosed with WS and her mother with a balanced 7q translocation [t(7:11)(q34;q13)]. Using DNA isolated from buccal smears obtained from several individuals in this family we were able to establish normal disomy at 7q in all family members except for the proband, in which we established hemizygosity at the elastin gene locus. We were also able to successfully infer normal disomy in an unborn child in this family. The rapid diagnostic procedure described here may have a variety of applications, including fine mapping of deletion breakpoints at 7q11.23 associated with WS.

Adult↗