Crisponi/cold‐induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. ...The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type‐3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype–phenotype relationships in CS/CISS‐like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1‐associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7‐related phenotypes.
Abstract
Context
Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with ...hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait.
Objective
To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI.
Design, Setting, and Participants
We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity.
Results
This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds.
Conclusions
ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.
Exome sequencing was used to investigate genes and mutational mechanisms contributing to primary ovarian insufficiency, and to gain insights into disease biology and underlying pathophysiology.
Rapid and reliable detection of severe acute respiratory syndrome coronavirus 2 mutations are significant to control the contagion and spread rate of the virus. We aimed to evaluate the N501Y ...mutation rate in randomly chosen positive patients with the polymerase chain reaction (PCR). The evaluation and analysis of the data with a retrospective approach in cases with mutations, in terms of public health, will contribute to the literature on the global pandemic that affects our society. Public health authorities will take the necessary precautions and evaluate the current situation. The N501Y mutation was detected in patients with positive Covid‐19 PCR test results. The positive samples were examined based on the 6‐carboxy‐fluorescein (FAM) channel in reverse transcription PCR (RT‐PCR) quantitation cycle (Cq) values as low Cq (<25), medium Cq (25–32), and high Cq (32–38) groups. In the study, 2757 (19.7%) of 13 972 cases were detected as mutation suspects and 159 (5.8%) of them were found to have mutations. The ages of the cases with mutations ranged from 1 to 88 years (mean age of 40.99 ± 17.55). 49.7% (n = 79) of the cases with mutations were male, and 50.3% (n = 80) were female. When the RT‐PCR‐Cq results were examined, it was seen that it varied between 11.3 and 35.03, with an average of 20.75 ± 3.32.
In ATP6V0A2‐related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa and typically associates with skeletal and neurological manifestations. The phenotype remains ...incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibres has not been studied in ATP6V0A2‐related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2‐related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and with elastic fibre anomalies. Our data will affect clinical management of patients with ATP6V0A2‐related cutis laxa.
The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and ...hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.
ObjectiveChildren with Down syndrome have a high incidence of major malformations and corrective surgery. Some patients do not need any surgery, while some cases are operated for several indications. ...There are few studies investigating the effect of maternal age on the phenotype of these children, despite the fact that increasing maternal age is a known risk factor for giving birth to Down syndrome. We aimed to investigate the incidence of surgery for major malformations and disorders in children with Down syndrome and its relationship with maternal age at birth. MethodsWe revised the records of 218 children with Down syndrome for maternal age at birth and for surgical interventions. ResultsThere were 84 children who had at least one operation with 38.5% incidence. A total of 49 children had cardiac surgery, 16 had gastrointestinal, 17 had head and neck area, 12 had ophthalmological, 12 had genitourinary, 5 had hernia, and 2 had orthopedic surgeries. The mean maternal age was 32.7 (minimum: 15; maximum: 44), and there was no significant difference between operated and non-operated groups for mean maternal ages (32.41 and 32.93, respectively; p=0.89). For any type of surgery, there was no significant difference between the groups with maternal ages 35 and over and those under 35. ConclusionsMaternal age at birth has no effect on the incidence of malformations and the probability of operation in Down syndrome.
A single-nucleotide polymorphism of the growth hormone 1 gene, GH1IVS4+90A>T (rs2665802), associated with short stature and a polymorphism of the growth hormone receptor gene, exon 3 deleted variant, ...associated with increased responsiveness to growth hormone have been reported previously. We aimed to investigate the frequency of both polymorphisms and their correlation to height in Turkish short children. Also, we aimed to evaluate the effect of exon 3 deleted variant on response to 1-year growth hormone therapy.
Children with idiopathic isolated growth hormone deficiency (n = 39) and with idiopathic short stature (n = 10) and 50 control subjects were evaluated for anthropometric parameters, annual growth velocity, and annual height gain. Growth hormone receptor gene polymorphisms were analyzed via multiplex polymerase chain reaction; growth hormone 1 gene polymorphism was analyzed via polymerase chain reaction and single-strand conformation polymorphism techniques.
The frequency of genotypes carrying the "A" allele was not significantly higher in the idiopathic isolated growth hormone deficiency group than in the idiopathic short stature and control groups (P = .03 for each). The exon 3 deleted variant genotype was significantly lower in the idiopathic short stature group compared to the control group (P = .01). There was no effect of exon 3 deleted variant, on response to the first-year growth hormone therapy.
In Turkish population, no correlation was found between the "A" allele of GH1IVS4+90A>T polymorphism and idiopathic isolated growth hormone deficiency and short stature, and a significant negative correlation was found between exon 3 deleted variant and idiopathic short stature and short stature. Exon 3 deleted variant has no effect on response to growth hormone treatment.
Spondylometaepiphyseal dysplasia short limb-abnormal calcification type (SMED-SL/AC) is a rare autosomal recessive disorder. It is a severe dwarfism syndrome with a characteristic feature of ...progressive calcification of epiphyseal and other cartilaginous tissues. It is caused by pathogenic variants in the DDR2 gene encoding the discoidin domain receptor tyrosine kinase 2. Thus far, 37 cases and 8 pathogenic variants have been reported. Most of the reported cases are of Middle Eastern and Puerto Rican origins. Only one Turkish case has been reported previously with a novel truncating variant p.(R489*). Here, we report 2 new cases, 1 with a novel variant p.(S311G) and 1 with a splice site variant c.2283+1G>A. In addition, we reviewed a previously reported case, and sequencing of stored DNA revealed the recently reported nonsense variant p.(R489*) as the underlying cause. Therefore, our data increase the number of SMED-SL/AC Turkish patients with molecular results to 4. Furthermore, we compared the features of Turkish patients with other reported cases and expanded the characteristics of the disorder with new features such as triventricular hydrocephalus, intracranial hemorrhage, hypopigmentation of hair, dry and scaly skin, arthralgia, and hypocalcemia. We also compared the pathogenic variants of Turkish patients with other variants, aiming to explain the mechanism leading to a more severe and early fatal course in Turkish patients.
Low estriol (uE3) levels in the second-trimester screening for Down syndrome may be the result of fetal demise, congenital abnormalities, or some genetic hormonal disorders of the fetus. Although ...X-linked ichthyosis, a microdeletion syndrome with mild ichthyosis, which causes steroid sulfatase (STS) deficiency, is the most common genetic cause, second-trimester screening tests calculate the risk for a less common and severe disorder known as the Smith Lemli Opitz syndrome (SLOS). We aimed to investigate the outcomes of pregnancies with low uE3 levels in Down syndrome screening and emphasize the high prevalence of STS deficiency instead of SLOS in such cases.
Fifteen pregnancies with very low uE3 levels and high risk for trisomy and/or SLOS in screening tests were evaluated and tested for STS deficiency and SLOS.
Seven of the pregnancies had STS microdeletion syndrome, while additional two cases were supposed to have STS gene mutation according to family and/or postnatal history. Although one fetal death was recorded, no chromosomal abnormality, SLOS, or congenital malformation was recorded in our series.
SLOS is a very severe and rare syndrome. The risk estimation for SLOS in screening tests causes stress for pregnant women and healthcare givers. We recommend the addition of risk estimation for STS deficiency when a low uE3 level is detected in the screening test.
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