Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, ...comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care.
We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported.
In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring.
ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.
The melanotrope cells in the pituitary gland of
Xenopus laevis are innervated by neurons containing neuropeptide Y (NPY). In the present study, the mechanism of action of NPY on the melanotropes has ...been investigated. NPY inhibited in vitro secretion from melanotropes in intact neurointermediate lobes as well as from isolated, single melanotropes. Inhibition of secretion from neurointermediate lobes was mimicked by the NPY analogues PYY and Leu
31,Pro
34NPY, whereas NPY(13–36) was inactive. Secretion from isolated melanotropes was inhibited by Leu
31,Pro
34NPY and NPY(13–36), but NPY(13–36) was 10-fold less potent than Leu
31,Pro
34NPY. Studies on isolated cells revealed that NPY and its analogues inhibited the occurrence of intracellular Ca
2+ oscillations with the same potency as they inhibited secretion from isolated cells. In addition to inhibiting basal secretion and spontaneous Ca
2+ oscillations, NPY inhibited the basal production of cyclic AMP. On the basis of these results it is proposed that NPY inhibits secretion from
Xenopus melanotropes by inhibiting cyclic AMP-dependent spontaneous Ca
2+ oscillations through a Y
1-like receptor.
The melanotrope cells in the pituitary gland of Xenopus laevis are innervated by neurons containing neuropeptide Y (NPY). In the present study, the mechanism of action of NPY on the melanotropes has ...been investigated. NPY inhibited in vitro secretion from melanotropes in intact neurointermediate lobes as well as from isolated, single melanotropes. Inhibition of secretion from neurointermediate lobes was mimicked by the NPY analogues PYY and Leu31,Pro34NPY, whereas NPY(13-36) was inactive. Secretion from isolated melanotropes was inhibited by Leu31,Pro34NPY and NPY(13-36), but NPY(13-36) was 10-fold less potent than Leu31,Pro34NPY. Studies on isolated cells revealed that NPY and its analogues inhibited the occurrence of intracellular Ca2+ oscillations with the same potency as they inhibited secretion from isolated cells. In addition to inhibiting basal secretion and spontaneous Ca2+ oscillations, NPY inhibited the basal production of cyclic AMP. On the basis of these results it is proposed that NPY inhibits secretion from Xenopus melanotropes by inhibiting cyclic AMP-dependent spontaneous Ca2+ oscillations through a Y1-like receptor.
Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. ...Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
X-linked forms of mental retardation (XLMR) include a variety of different disorders and may account for up to 25% of all inherited cases of mental retardation. So far, seven X-chromosomal genes ...mutated in nonspecific mental retardation (MRX) have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM4SF2, OPHN1 and PAK3 (refs 2-9). The products of the latter two have been implicated in regulation of neural plasticity by controlling the activity of small GTPases of the Rho family. Here we report the identification of a new MRX gene, ARHGEF6 (also known as αPIX or Cool-2), encoding a protein with homology to guanine nucleotide exchange factors for Rho GTPases (Rho GEF). Molecular analysis of a reciprocal X/21 translocation in a male with mental retardation showed that this gene in Xq26 was disrupted by the rearrangement. Mutation screening of 119 patients with nonspecific mental retardation revealed a mutation in the first intron of ARHGEF6 (IVS1-11T→C) in all affected males in a large Dutch family. The mutation resulted in preferential skipping of exon 2, predicting a protein lacking 28 amino acids. ARHGEF6 is the eighth MRX gene identified so far and the third such gene to encode a protein that interacts with Rho GTPases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
High-resolution genome-wide array analysis enables detailed screening for cryptic and submicroscopic imbalances of microscopically balanced de novo rearrangements in patients with developmental delay ...and/or congenital abnormalities. In this report, we added the results of genome-wide array analysis in 54 patients to data on 117 patients from seven other studies. A chromosome imbalance was detected in 37% of all patients with two-breakpoint rearrangements. In 49% of these patients, the imbalances were located in one or both breakpoint regions. Imbalances were more frequently (90%) found in complex rearrangements, with the majority (81%) having deletions in the breakpoint regions. The size of our own cohort enabled us to relate the presence of an imbalance to the clinical features of the patients by using a scoring system, the De Vries criteria, that indicates the complexity of the phenotype. The median De Vries score was significantly higher (P=0.002) in those patients with an imbalance (5, range 1-9) than in patients with a normal array result (3, range 0-7). This study provides accurate percentages of cryptic imbalances that can be detected by genome-wide array analysis in simple and complex de novo microscopically balanced chromosome rearrangements and confirms that these imbalances are more likely to occur in patients with a complex phenotype.
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