Developmental and epileptic encephalopathies (DEEs) refer to a group of severe epileptic syndromes characterized by seizures as well as a developmental delay which can be a consequence of the ...underlying etiology and/or the epileptic encephalopathy. The genes responsible for DEEs are numerous and their number is increasing since the availability of Next-Generation Sequencing. Pathogenic variants in GRM7, encoding the metabotropic glutamate receptor 7, were recently shown as a cause of a severe DEE with autosomal recessive inheritance. To date, only ten patients have been reported in the literature, generally with severe phenotypes including early-onset epilepsy, microcephaly, brain anomalies, and spasticity. We report here 5 patients from 3 independent families with biallelic variants in the GRM7 gene. We review the literature and provide further elements for the understanding of the genotype-phenotype correlation of this rare syndrome.
Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, ...MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.
Abstract Objective To assess whether the area under the curve of temporal estradiol measurements (AUCEM) during cycles of assisted reproductive technology (ART) can be used to predict failure of ...implantation and clinical pregnancy. Methods In a prospective study, women aged 24–39 years undergoing ART at a center in Turkey were enrolled between January and December 2014. Eligible patients had a regular menstrual cycle, normal levels of serum prolactin, and no hormone treatment within the past 3 months. The area under the curve of the time course of estradiol measurements was calculated for each participant, and assessed for its ability to predict successful implantation. Results Among 282 participants, 109 (38.6%) women had successful implantation. There was a significant difference between the two groups of women in AUCEM, estradiol per day (AUCEM divided by duration of stimulation), and endometrial thickness on the day of human chorionic gonadotropin administration ( P < 0.05 for all). Conclusion The area under the curve of estradiol measurements during ART cycles might be useful for predicting failure of implantation and clinical pregnancy.
Runs of homozygosity (ROH) are consecutive homozygous genotypes, which may result from population inbreeding or consanguineous marriages. ROH enhance the expression of recessive traits.
We mapped ROH ...in a case control study of women delivering at term compared with women delivering at or before 34 wk gestation. Gene sets known to be important in risk of preterm birth were examined for their overlap with identified ROH segments.
While we found no evidence of increased burden of ROH or copy number variations in mothers delivering at or before 34 wk compared with term, we identified 424 genome-wide 50 kb segments with significant difference in abundance of overlapping ROH segments in cases vs. controls, P < 0.05. These regions overlap 199 known genes. We found preterm birth associated genes (CXCR4, MYLK, PAK1) and genes shown to have an evolutionary link to preterm (CXCR4, PPP3CB, C6orf57, DUSP13, and SLC25A45) with significant differences in abundance of overlapping ROH blocks in cases vs. controls, P < 0.001.
We conclude, while we found no significant burden of ROH, we did identify genomic regions with significantly greater abundance of ROH blocks in women delivering preterm that overlapped genes known to be involved in preterm birth.
The Mediator multiprotein complex functions as a regulator of RNA polymerase II–catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease‐causing variants in ...MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828–833
Interstitial deletions of the short and long arms of chromosome 5 are rare cytogenetic abnormalities. The 5p distal deletion is a genetic disorder characterized by a high‐pitched cat‐like cry, ...microcephaly, epicanthal folds, micrognathia, severe intellectual disability and motor delays. Previously, more than 46 patients with the 5q deletion have been reported. Here, we report de novo interstitial deletions involving 5p14.1–p15.2 and 5q14.3–q23.2 in a patient with multiple congenital abnormalities, including blepharophimosis, arthrogryposis, short neck, round face, pelvic kidney, agenesis of the corpus callosum, and clubfoot. The deletions were characterized using GTG banding and aCGH microarray analysis. Concurrent 5p and 5q interstitial deletions in humans have not been previously reported. We also discussed the relationship between the 5q deleted region and clubfeet.
The aim of this study was to assess whether the time from the menstrual day at embryo transfer to expected menstrual cycle (TETEMC) is associated with the implantation in women with regular cycles or ...not.
Forty women with successful implantation and forty women without implantation with regular cycles were randomly selected from prospectively collected database of assisted reproductive technology clinic of Zeynep Kamil Women And Children's Health Training and Research Hospital. TETEMC was calculated for each case to assess relationship with the successful implantation.
Comparison of groups revealed significant differences with regard to TETEMC and the menstrual period (p<0.05). In ROC analyses both the TETEMC (AUC=0.824, p<0.001) and the menstrual period (AUC=0.797, p<0.001) were significant predictors for clinical pregnancy. Cut off value for the menstrual period was found to be 27.5 days with 82.6% sensitivity and 65% specificity. Cut off value for TETEMC was 11.5 days with 75% sensitivity and 63.2% specificity.
Longer menstrual cycle and the TETEMC seem to be associated with the implantation failure.
To assess the relationship between the estrogen-progesterone alterations before and after ovulation trigger and treatment success in intrauterine insemination (IUI) cycles.
Two hundred fifty-one ...women with infertility underwent ovulation induction followed by IUI. For all subjects, estradiol and progesterone concentrations were evaluated on the trigger and IUI day. The results were analyzed to assess the relationship between hormone levels and positive pregnancy test.
There were 34 women with a positive pregnancy test following controlled ovarian stimulation and IUI cycle. Estradiol and progesterone levels on the trigger day and the day of IUI were compared within groups with and without positive pregnancy tests. The comparison revealed significantly increased levels of progesterone after trigger in both groups; however, although there were estradiol level drops in both groups, the drop in the group with negative pregnancy tests was statistically significant.
Significant drops in estradiol concentrations after ovulation trigger are associated with IUI cycle treatment failure.
Hereditary angioedema (HAE) is characterised by recurrent episodes of angioedema and can be fatal.
The present study aimed to screen HAE.
A total of 60 individuals were screened. The frequency and ...severity of symptoms were scored from 0 to 8. Measurements were taken of C4 and C1 esterase inhibitor protein (C1-INH) levels. Mutation in the C1 inhibitor gene was examined in 9 patients with HAE.
A positive correlation between the C1 esterase inhibitor protein levels and C4 level was detected in the group as a whole (p < 0.001, r = 0.725, n = 60). Anegative correlation between the C1 esterase inhibitor protein level and severity score was observed in the whole group (p < 0.001, r = -0.486, n = 60). A negative correlation was also detected in the entire group between the C4 level and severity score (p = 0.002, r = -0.389, n = 60). In the patients with HAE, a positive correlation between the C1 esterase inhibitor protein level and C4 levels was detected (p = 0.034, r = 0.705, n = 9). A heterozygous c. 601A > T nonsense variant was identified at the C1 esterase inhibitor gene-SERPING1-in patients with Type 1 HAE.
It is well known that there is a prolonged delay in the diagnosis of HAE. The present study demonstrates that it is very important and even life-saving to screen for HAE on the basis of an index case.
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