LHX2 haploinsufficiency causes a variable neurodevelopmental disorder.

Purpose: LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date.

Methods: Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems.

Rare and de novo duplications containing TCF20 are associated with a neurodevelopmental disorder.

Transcriptor co-activator factor 20 gene (TCF20) encodes a nuclear chromatin-binding protein involved in regulation of gene expression. In human pathology, pathogenic variants or deletions in TCF20 were identified in patients with developmental delay, variable intellectual disability and behavioral impairment (OMIM: 618430). The shared core phenotype includes developmental delay, hypotonia, motor delay, autism spectrum disorders, neurobehavioral anomalies, neurological features such as ataxia, seizures, movement disorders, structural brain anomalies, craniofacial features and various congenital anomalies.

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.

Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized.

Structural abnormalities of chromosome 8 and fetoplacental discrepancy: A second case report and review of fetal phenotype of 8p inverted duplication deletion syndrome.

We described a new second case of fetoplacental discrepancy involving first trimester prenatal detection of mosaic isochromosome i (8) (q10). A 32-year-old woman underwent chorionic villous sampling because of increased fetal nuchal translucency. Analysis of direct chromosome preparations was performed by R-banding and FISH using subtelomeric, centromeric and whole chromosome painting probes for chromosome 8 showing the presence of an isochromosome 8q with a complex, female mosaic karyotype: mos 46,XX,i (8) (q10)[13]/46,XX,del (8) (p23)[10].

Variable neurodevelopmental and morphological phenotypes of carriers with 12q12 duplications.

Background: Variable size deletions affecting 12q12 have been found in individuals with neurodevelopmental disorders (NDDs) and distinct facial and physical features. For many genetic loci affected by deletions in individuals with NDDs, reciprocal duplications have been described. However, for the 12q12 region, there are no detailed descriptions of duplication cases in the literature.

11q24.2q24.3 microdeletion in two families presenting features of Jacobsen syndrome, without intellectual disability: Role of FLI1, ETS1, and SENCR long noncoding RNA.

This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID).

Pitfalls in the biological diagnosis of common hemoglobin disorders.

In West-European countries, hemoglobin disorders are no more rare diseases. Programs for diagnosis of heterozygous carriers have been established to prevent cases with major sickle cell disease or thalassemias. These studies have been done essentially by high performance liquid chromatography on cation-exchange columns and electrophoresis (mostly capillary electrophoresis).

Updates of the HbVar database of human hemoglobin variants and thalassemia mutations.

HbVar (http://globin.bx.psu.

Pitfalls in the genetic diagnosis of Hb S.

Patients homozygous for Hb S need to be properly identified to start as early as possible a treatment that should avoid complications. For prevention and genetic counseling, carriers of Hb S have to be screened. Hb S is easily detected by several analytical systems, but other variants, usually harmless, may behave as Hb S, leading to false positive diagnosis.

Two new class III G6PD variants [G6PD Tunis (c.920A>C: p.307Gln>Pro) and G6PD Nefza (c.968T>C: p.323 Leu>Pro)] and overview of the spectrum of mutations in Tunisia.

We screened 423 patients referred to our laboratory after hemolysis triggered by fava beans ingestion, neonatal jaundice or drug hemolysis. Others were asymptomatic but belonged to a family with a history of G6PD deficiency. The determination of enzymatic activity using spectrophotometric method, revealed 293 deficient (143 males and 150 females).

Erythrocyte density in sickle cell syndromes is associated with specific clinical manifestations and hemolysis.

Dense, dehydrated red blood cells (DRBCs) are a characteristic feature of sickle-cell disease (SCD). DRBCs play a role in the pathophysiology of SCD acute and chronic organ damage because of heightened tendency to undergo polymerization and sickling because of their higher hemoglobin S concentration. Relations between red cell density (assessed with phthalate density-distribution profile method) and several hematologic, biochemical, genetic parameters, and clinical manifestations were studied in a large cohort of homozygous patients.

Estimation of the difference in HbF expression due to loss of the 5' δ-globin BCL11A binding region.

BCL11A was the focus of recent studies on its inhibiting effect when bound onto the β-globin cluster in the mechanism of hemoglobin switching and HbF downregulation. We examined a cohort of 10 patients displaying different HbF levels and short deletions within the γβ-δ intergenic region to find a possible correlation with the BCL11A binding site located 5' to the δ-globin gene. Precise characterization of deletions was achieved using a custom DNA-array chip and breakpoint sequencing.

Glucose-6-phosphate dehydrogenase (G6PD) mutations database: review of the "old" and update of the new mutations.

In the present paper we have updated the G6PD mutations database, including all the last discovered G6PD genetic variants. We underline that the last database has been published by Vulliamy et al. [1] who analytically reported 140 G6PD mutations: along with Vulliamy's database, there are two main sites, such as http://202.

Comparison of two known chromosomal rearrangements in the δβ-globin complex with identical DNA breakpoints but causing different Hb A(2) levels.

We report three cases with very heterogeneous Hb A(2) levels caused by known chromosomal rearrangements in the β-globin locus. These rearrangements had their breakpoints at the same region in the δ gene, leading either to the Senegalese δ(0)β(+)-thalassemia (δ(0)β(+)-thal) deletion or to an insertion of a δ gene, known as Anti-Lepore. One patient showed, apart from drastically increased Hb A(2) values of 17.

Practical approach for characterization of glucose 6-phosphate dehydrogenase (G6PD) deficiency in countries with population ethnically heterogeneous: description of seven new G6PD mutants.

We present a rapid strategy based on Restriction Fragment Length Polymorphism (RFLP) analysis to characterize the more frequent glucose 6-phosphate dehydrogenase (G6PD) variants observed in a population with high gene flow. During a study involving more than 600 patients, we observed mainly G6PD A(-) (c.202G>A, c.

Abnormal haemoglobins: detection & characterization.

Haemoglobin (Hb) abnormalities though quite frequent, are generally detected in populations during surveys and programmes run for prevention of Hb disorders. Several methods are now available for detection of Hb abnormalities. In this review, the following are discussed: (i) the methods used for characterization of haemoglobin disorders; (ii) the problems linked to diagnosis of thalassaemic trait; (iii) the strategy for detection of common Hb variants; and (iv) the difficulties in identification of rare variants.

Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Jeddah, Kingdom of Saudi Arabia.

Background: The development of polymerase chain reaction (PCR)-based methods for the detection of known mutations has facilitated detecting specific red blood cell (RBC) enzyme deficiencies. We carried out a study on glucose-6-phosphate dehydrogenase (G6PD) deficient subjects in Jeddah to evaluate the molecular characteristics of this enzyme deficiency and the frequency of nucleotide1311 and IVS-XI-93 polymorphisms in the glucose-6-phosphate dehydrogenase gene.

Results: A total of 1584 unrelated Saudis (984 neonates and 600 adults) were screened for glucose-6-phosphate dehydrogenase deficiency.

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach.

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system.

A rare G6PD variant (c.383T>G; p.128Leu>Arg) with a molecular pathophysiological mechanism similar to that of G6PD A- (68Val>Met, 126Asn>Asp).

We report the second documented observation of a rare class-III variant, we named G6PD Pyrgos, [c.383 T>G, p.128Leu>Arg] found in a Greek family.