Molecular and clinical analyses with neuropsychological assessment of a case of del(10)(q26.2qter) without intellectual disability: Genomic and transcriptomic combined approach and review of the literature.

Terminal deletion of the long arm of the chromosome 10 is a rare but well known abnormality, with a large phenotypic variability. Very few data are available about subtelomeric deletion 10q26 patients without intellectual disability. Herein, we report the case of a young adult with a classical 10q26.

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

Background: Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is also associated with autism spectrum disorders. Previous studies implicated BKCa channels in the neuropathogenesis of FXS, but the main question was whether pharmacological BKCa stimulation would be able to rescue FXS neurobehavioral phenotypes.

Methods And Results: We used a selective BKCa channel opener molecule (BMS-204352) to address this issue in Fmr1 KO mice, modeling the FXS pathophysiology.

Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration.

Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date.

Combined deletion of two Condensin II system genes (NCAPG2 and MCPH1) in a case of severe microcephaly and mental deficiency.

7qter deletion syndrome includes prenatal and/or postnatal growth retardation, microcephaly, psychomotor delay or mental retardation and a characteristic dysmorphism. If clinical features are well described, the molecular mechanisms underlying the 7qter deletion syndrome remain unknown. Those deletions usually arise de novo.

Dysregulation of FOXG1 pathway in a 14q12 microdeletion case.

"FOXG1 syndrome" includes postnatal microcephaly, severe intellectual disability with absence of language and agenesis of the corpus callosum. When the syndrome is associated with large 14q12q13 deletions, the patients present characteristic facial dysmorphism. Although all reports were based on genomic analysis, recently a FOXG1 regulatory elements deletion, associated with down regulated mRNA, suggested an implication of FOXG1 pathway.

Pure proximal deletion of chromosome 21 and kyphosis.

We report on two unrelated patients with a proximal deletion of the long arm of chromosome 21. The deletion encompassed 14.5Mb of DNA.

PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.

The Phox2b gene is necessary for autonomic nervous-system development. Phox2b-/- mice die in utero with absent autonomic nervous system circuits, since autonomic nervous system neurons either fail to form or degenerate. We first identified the Phox2b human ortholog, PHOX2B, as the gene underlying congenital central hypoventilation syndrome (CCHS, or Ondine curse), with an autosomal dominant mode of inheritance and de novo mutation at the first generation.

PHOX2B gene mutation in a patient with late-onset central hypoventilation.

Congenital central hypoventilation syndrome, which is related to abnormal autonomic control of breathing and typically manifests at birth, was recently associated with PHOX2B gene mutations. In contrast, central hypoventilation with later onset constitutes a poorly defined group of unknown etiology. Here, we report on the identification of a de novo heterozygous PHOX2B mutation in a patient with central hypoventilation manifesting in childhood.

X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.

A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2-base-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to beta-neurexins.

Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse).

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase.

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b.