Investigation of the Relationship Between Religious Attitude and Postpartum Physical and Perineal Pain in Iran.

Postpartum pain is one of the most important and common problems of postpartum mothers who resort to non-pharmacological strategies to relieve it due to the side effects of painkillers. This study was conducted to investigate the relationship between religiosity and postpartum physical and perineal pain. The sample size in this cross-sectional study was 101 women giving birth in educational and medical centers of Shiraz, Iran, that was selected by purposive-convenience sampling. Then, a questionnaire was completed for each of them including demographic characteristics, religious attitude, and visual scale of postpartum pain. Data were analyzed by SPSS software. The frequency of the majority of the research population was found at moderate religious attitudes 65.4% (72 individuals). There is a positive and Statistical inverse correlation between religious attitude and perineal pain. According to Fisher's test, in mothers with a high religious attitude, 9.7% had severe perineal pain, 41.9% had moderate pain, and 48.4% had mild pain (p = 0.001). Besides, in the case of physical pain, 3.2%, 35.5%, and 61.3% had severe, moderate, and mild pain, respectively. Regarding physical pains, with the increase in the level of mothers' religious attitude, physical pains also decreased, but the statistical relationship was not significant (p = 0.32). The results showed that the religiosity and spirituality of pregnant women have relieving effects on postpartum pain. Therefore, more attention to the spiritual dimension of human existence and planning to improve it using prayer therapy, dhikr, and meditation is suggested as a strategy to deal with the fear of pain and childbirth and reduce psychological and physical changes before and after childbirth. These findings apply to women with ectopic pregnancies in Iran.

Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.

The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development. We show that Zak is expressed in the developing limbs and that a CRISPR/Cas-mediated knockout of the two Zak isoforms is embryonically lethal in mice. In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene. Our results identify ZAK as a key player in mammalian limb patterning and demonstrate the rapid utility of CRISPR/Cas genome editing to assign causality to human mutations in the mouse in <10 wk.

Targeted next generation sequencing reveals genetic defects underlying inherited retinal disease in Iranian families.

Purpose: Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous showing progressive retinal cell death which results in vision loss. IRDs include a wide spectrum of disorders, such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), cone-rod dystrophy (CRD), and Stargardt disease (STGD1). Methods: In this study, we performed targeted next-generation sequencing based on molecular inversion probes (MIPs) that allowed the sequence analysis of 108 IRD-associated genes in 50 Iranian IRD probands. Results: The sequencing and variant filtering led to the identification of putative pathogenic variants in 36 out of 50 (72%) probands. Among 36 unique variants, we identified 20 novel variants in 15 genes. Four out of 36 probands carry compound heterozygous variants, and 32 probands carry homozygous variants. Conclusions: Employing a cost-effective targeted next-generation sequencing procedure, we identified the genetic causes of different retinal disorders in the majority of Iranian families in this study.

The Relationship Between Body Mass Index (BMI) and Menstrual Disorders at Different Ages of Menarche and Sex Hormones.

OBJECTIVE: The present research aimed to study the relationship between body mass index and menstrual disorders at different ages of menarche and sex hormones. METHODS: In this cross-sectional study, 2000 girls aged between 9 and 18 in all levels were selected through cluster sampling in Shiraz. Data were collected using demographic characteristics, menstrual disorders, body mass index and hormones' measure questionnaires. To analyze the data, we used SPSS 16 and Chi-square test. RESULTS: A total of 1024 (51.2%) out of 2000 subjects had normal BMI and the smallest group belonged to 26 subjects (1.3%) with BMI ≤ 30. There is a significant relationship between body mass index, menstrual cycle length (p = 0.006), spotting (p = 0.005), passing clots (p = 0.001) and menstrual bleeding (p = 0.04), and this relationship is insignificant between body mass index and duration of bleeding (p = 0.95), amenorrhea (p = 0.03), dysmenorrhea (p = 0.26) and menstrual regularity (p = 0.95). Investigating the relationship between body mass index and some of sex hormones shows that there is no significant relationship among BMI and TSH (p = 0.94), FSH (p = 0.21), LH (p = 0.21), Prolactin (p = 0.97), Testosterone (p = 0.66), and DHEAS (p = 0.94). CONCLUSIONS: A significant relationship among BMI and menstrual cycle length, spotting, passing clots and menstrual bleeding, and was insignificant with sex hormones.

A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation.

Synpolydactyly (SPD) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and an additional digit in the syndactylous web. In most cases SPD is caused by heterozygous mutations in HOXD13 resulting in the expansion of a N-terminal polyalanine tract. If homozygous, the mutation results in severe shortening of all metacarpals and phalanges with a morphological transformation of metacarpals to carpals. Here, we describe a novel homozygous missense mutation in a family with unaffected consanguineous parents and severe brachydactyly and metacarpal-to-carpal transformation in the affected child. We performed whole exome sequencing on the index patient, followed by Sanger sequencing of parents and patient to investigate cosegregation. The DNA-binding ability of the mutant protein was tested with electrophoretic mobility shift assays. We demonstrate that the c.938C>G (p.313T>R) mutation in the DNA-binding domain of HOXD13 prevents binding to DNA in vitro. Our results show to our knowledge for the first time that a missense mutation in HOXD13 underlies severe brachydactyly with metacarpal-to-carpal transformation. The mutation is non-penetrant in heterozygous carriers. In conjunction with the literature we propose the possibility that the metacarpal-to-carpal transformation results from a homozygous loss of functional HOXD13 protein in humans in combination with an accumulation of non-functional HOXD13 that might be able to interact with other transcription factors in the developing limb.

Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations.

OBJECTIVE: Crohn's disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified 163 susceptibility loci to IBD in Caucasians, however there are limited studies in other populations. METHODS: We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls. RESULTS: We confirmed four previously reported loci: TNFSF15, IL23R, the major histocompatibility complex region, and the RNASET2-FGFR1OP-CCR6 region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10(-14)), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10(-10)) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10(-9)), implicating ATG16L2 and/or FCHSD2 as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of ATG16L2 with stronger association (OR=1.61, combined p=2.44×10(-12)) than rs11235667, suggesting ATG16L2 as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10(-5))) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans. CONCLUSIONS: Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.

Association of CETP Taq1B and -629C > A polymorphisms with coronary artery disease and lipid levels in the multi-ethnic Singaporean population.

BACKGROUND: Hyperlipidaemia is a major risk factor for coronary artery disease (CAD) and cholesteryl ester transfer protein (CETP) gene polymorphisms are known to be associated with lipid profiles. METHODS: In this study, we investigated the association of two polymorphisms in the CETP, Taq1B (rs708272) and -629C > A (rs1800775), with CAD and lipid levels HDL-C in 662 CAD + cases and 927 controls from the Singapore population comprising Chinese, Malays and Indians. RESULTS: TaqB2 frequency was significantly lowest in the Malays (0.43) followed by Chinese (0.47) and highest in the Indians (0.56) in the controls. The B2 allele frequency was significantly lower in the Chinese CAD + cases compared to the controls (p = 0.002). The absence of the B2 allele was associated with CAD with an OR 2.0 (95% CI 1.2 to 3.4) after adjustment for the confounding effects of age, smoking, BMI, gender, hypertension, dyslipidemia and diabetes mellitus. The B2 allele was significantly associated with higher plasma HDL-C levels in the Chinese men after adjusting for confounders. Associations with plasma apoA1 levels were significant only in the Chinese men for Taq1B and -629C > A. In addition, the Taq1B polymorphism was only associated with plasma Apo B and Lp(a) in the Malay men. Significant associations were only found in non-smoking subjects with BMI <50th percentile. In this study, the LD coefficients between the Taq1B and -629C > A polymorphisms seemed to be weak. CONCLUSION: The absence the Taq1B2 allele was associated with CAD in the Chinese population only and the minor allele of the Taq1B polymorphism of the CETP gene was significantly associated with higher plasma HDL-C levels in Chinese men.

Quantitative determination of SLC2A1 variant functional effects in GLUT1 deficiency syndrome.

OBJECTIVE: The goal of this study is to demonstrate the utility of a growth assay to quantify the functional impact of single nucleotide variants (SNVs) in SLC2A1, the gene responsible for Glut1DS. METHODS: The functional impact of 40 SNVs in SLC2A1 was quantitatively determined in HAP1 cells in which SLC2A1 is required for growth. Donor libraries were introduced into the endogenous SLC2A1 gene in HAP1-Lig4KO cells using CRISPR/Cas9. Cell populations were harvested and sequenced to quantify the effect of variants on growth and generate a functional score. Quantitative functional scores were compared to 3-OMG uptake, SLC2A1 cell surface expression, CADD score, and clinical data, including CSF/blood glucose ratio. RESULTS: Nonsense variants (N = 3) were reduced in cell culture over time resulting in negative scores (mean score: -1.15 ± 0.17), whereas synonymous variants (N = 10) were not depleted (mean score: 0.25 ± 0.12) (P < 2e-16). Missense variants (N = 27) yielded a range of functional scores including slightly negative scores, supporting a partial function and intermediate phenotype. Several variants with normal results on either cell surface expression (p.N34S and p.W65R) or 3-OMG uptake (p.W65R) had negative functional scores. There is a moderate but significant correlation between our functional scores and CADD scores. INTERPRETATION: Cell growth is useful to quantitatively determine the functional effects of SLC2A1 variants. Nonsense variants were reliably distinguished from benign variants in this in vitro functional assay. For facilitating early diagnosis and therapeutic intervention, future work is needed to determine the functional effect of every possible variant in SLC2A1.

Diagnostic yield of exome sequencing in congenital vertical talus.

BACKGROUND: Congenital vertical talus (CVT), also known as "rocker-bottom foot", is a rare foot deformity associated with a dislocation of the talonavicular joint. Although genetic causes of CVT have been described in single isolated and syndromic families, whole-exome sequencing (WES) of large cohorts have not yet been reported. METHODS: In this study, 62 probands with CVT were evaluated for likely causative single nucleotide variants (SNVs) and copy number variants (CNVs) using WES. Segregation of variants within families was determined by Sanger sequencing. RESULTS: In this cohort, CVT occurred as an isolated anomaly in 75.8% (47/62) and was familial in 19.3% (12/62) of cases. Analysis of WES data led to the identification of likely causative variants in known disease genes in 30.6% (19/62) of all CVT probands. More than one proband had likely causative SNVs in TSHZ1, GDF5, and LMX1B. Only two probands had likely causative CNVs: a chromosome 12q13.13 deletion of the 5' HOXC gene cluster, and a chromosome 18q22.3q23 deletion involving TSHZ1. Familial CVT was strongly predictive of identifying a molecular diagnosis [75% (9/12) of familial cases compared to 20% (10/50) of non-familial cases (Chi-square test, P-value = 0.0002)]. There was no difference in the solved rate based on isolated or syndromic presentation, unilateral or bilateral affectation, or sex. CONCLUSIONS: CVT is genetically heterogeneous and more often caused by SNVs than CNVs. There is a high yield of WES in familial CVT cases (∼75%). Additional research is needed to identify the causes of sporadic CVT, which had much lower solved rates.

Investigation of the role of herbal medicine, acupressure, and acupuncture in the menopausal symptoms: An evidence-based systematic review study.

BACKGROUND: Menopause is an important physiological phenomenon in women's lives. Women's concern about taking the hormone treatment to ease menopausal symptoms is increasing. Over the past decade, the use of complementary and alternative medicine for the treatment of menopausal problems instead of hormone therapy has increased. OBJECTIVE: This study aimed to investigate the role of herbal medicine, acupressure, and acupuncture in the menopausal symptoms. METHODS: Data source: related articles were searched from internal scientific databases and external databases of "Web of Scopus, Cochrane, PubMed, Science Direct, Ovid, and Google scholar." STUDY ELIGIBILITY CRITERIA: The keywords such as menopause, menopausal symptoms, complementary menopausal medicine, acupuncture in menopause, herbal medicine in menopause, and acupuncture in menopause were searched in the studies from 1987 to 2019. Exclusion criteria were inadequate information in the study, lack of access to full-text articles, animal studies, and reports. At the end of the search, 145 articles out of a total of 400 articles were reviewed. RESULTS: In various studies, different herbs such as licorice, valerian, soy, sage, ginseng, etc., were used to improve menopausal symptoms. In addition, acupuncture and acupressure were used to reduce menopausal symptoms. CONCLUSION: The efficacy and use of complementary and alternative medicine, along with other classical medicine care, can be a new model for improving menopausal symptoms in women. It is recommended that further clinical and review studies be conducted to develop complementary and alternative medicine.

Determining genetic variants in children and adolescents suffering from tetralogy of Fallot with a positive family history: methodology.

BACKGROUND AND AIM: Congenital heart disease (CHD) affects near 1% of all live births and is considered to be the main reason of morbidity and mortality in early childhood. In this study, we investigated molecular genetics factors associated with Tetralogy of Fallot (TOF) using high throughput technologies in the consanguineous families with at least 2 affected individual. METHOD: This family study started in March 2017 to May 2018 in pediatric cardiovascular research center, Cardiovascular Research Institute, Isfahan, Iran. After obtaining informed consent, we invited families who had at least 2 individuals in one generation or previous generations with familial marriage history and they were included in the study. Genomic DNA was extracted from peripheral blood lymphocytes of the patient and samples were investigated for structural variations such as deletion or duplication in the genome using single nucleotide polymorphism array (SNP array). In the next step, if the SNP array is negative, next generation study will be performed in the propend and after analyzing the raw data and filtering for rare pathogenic variants. RESULTS: In this study, totally 5 families were evaluated. All affected and unaffected individuals of each family included in the pedigree.  This study comprised 14 subjects (9 males and 5 females; 8.92 ± 6.21 years old). Baseline characteristics and clinical data of the study subjects are presented in Table 1. The prevalence of consanguineous marriage is 92.2% among parents, 71.4% among mother grandparents and 28.6% among father grandparents. 64.3 % of our participants have sibling with similar disease. The prevalence of atrial septal defect (ASD), ventricular septal defect (VSD), and arrhythmia and TOF was 7.1%. CONCLUSION: We found some families with 2 or more CHD and with a high rate of consanguineous marriage and probably suffering from a genetic predisposition. We aim to exam them further with next generation study (NGS) to find any genetic defect and then to exam other CHD's in our region. Key words: gene mutations, children, adolescents, tetralogy of Fallot, family history.

Investigation of correlation between religious attitude and mother-adolescent girls conflict.

BACKGROUND: Religion is considered as one of the factors influencing one's behavior and cognition and plays an important role in shaping the individual's lifestyle. People with religious beliefs, due to less stress, may have less conflict with others. OBJECTIVE: Comparison of adolescents with high and low religious attitudes in terms of conflict with mother. METHODOLOGY: This is a cross-sectional, analytic, epidemiological study on girls aged between 15 to 18 years in middle and high schools of Shiraz. The sample size, with a percentage of conflict in a sample of 86 pilots, was 509. Data collection tools included a demographic questionnaire, conflict tactics scale parents (CTSP), and religious attitude questionnaire. RESULTS: There was no significant relationship between religious attitude and individuals' reasoning tactics (P = 0.072), and physical aggression tactics (P = 0.83) of the girls with mother conflict resolution. However, there was a significant relationship between religious attitude and verbal aggression tactics (P = 0.83) of adolescents and mothers (P = 0.04(. There was a significant difference between religious attitudes and total the girls with mother conflict resolution scale (P = 0.003). Relationship between religious attitude and individuals' reasoning tactics in conflict resolution (P = 0.072) and physical aggression tactics (P = 0.83) of self and mother was not seen significant relationship. CONCLUSION: The majority of girls (91.2%) had a moderate religious attitude (48.4%) at low levels of conflict. There was a significant relationship between religious attitude and the total score of There was no significant relationship between religious attitude and individuals' reasoning tactics (P = 0.072) and physical aggression tactics (P = 0.83) of the girls with mother conflict resolution conflict.

The effect of aromatherapy on mental, physical symptoms, and social functions of females with premenstrual syndrome: A randomized clinical trial.

OBJECTIVE: This study was designed to compare the effect of aromatherapy with Rosa Damascena and Citrus Aurantium blossom on psychological and physical symptoms and social functions of females with premenstrual syndrome. MATERIALS AND METHODS: This double-blind clinical trial was conducted on 95 students. They were randomly divided into three aromatherapy groups (aromatherapy with 4% concentration of Rosa Damascena and 0.5% concentration of Citrus Aurantium blossom essential oil) and aromatherapy with sweet almond oil (as control group). Premenstrual Symptoms Screening Tool questionnaire (PSST) was completed before and during the first and second month of the intervention. Data were analyzed by SPSS software version 22. RESULTS: After intervention, the scores of mental symptoms decreased in all three groups and this decrease was significant in both Citrus Aurantium (P = 0.004) and Rosa Damascena groups (P = 0.007). The score of physical symptoms was decreased in all three groups but it was significant only in the Rosa Demecensa group (P = 0.042). The reduction of effect of symptoms on social function was observed in two intervention groups which were significant only in Rosa Damascena group (P < 0.001). CONCLUSION: Essential oils of Rosa Damascena and Citrus Aurantium were both effective in improving the symptoms of premenstrual syndrome but the effect of Rosa Damascena, with regard to improvement of symptoms of premenstrual syndrome was more than that of Citrus Aurantium in all psychological, physical, and social aspects.

Precision Health Resource of Control iPSC Lines for Versatile Multilineage Differentiation.

Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users demonstrated versatility by generating kidney organoids, T lymphocytes, and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole-genome sequencing-based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harbored at least one pre-existing or acquired variant with cardiac, neurological, or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cells from six tissues for disease modeling, and variant-preferred healthy control lines were identified for specific disease settings.

Cornelia de lange syndrome.

BACKGROUND: Cornelia de Lange syndrome (CDLS) is a rare multiple congenital anomaly syndrome characterized by a distinctive facial appearance, developmental delay, growth retardation, low birth weight, skeletal formation anomaly, and hirsutism. CASE: Here for the first time a case of CDLS from Iran, a 15-week-old male infant who was refereed as a case of multiple congenital anomalies. Clinical investigation showed that the child was a case of CDLS. CONCLUSION: This is the first case report with CDLS in Iran.

Bloom's syndrome in a 12-year-old Iranian girl.

BACKGROUND: Bloom's syndrome, an autosomal recessive inherited disorder, belongs to the group of chromosomal breakage syndromes. The clinical diagnosis of BS is confirmed cytogenetically. Its frequency in the general population is unknown but it is common in eastern European Ashkenazi Jews. CASE REPORT: A 12-year-old girl was referred to us because of short stature. She was the second child of the first cousin marriage. She had a slender body frame, short stature, and microcephaly. Her face was long and narrow with prominent nose, and malar and mandibular hypoplasia. The spots of hyper and hypo pigmentation were observed in the trunk and limbs. Telangectasia spots were observed in some areas of the trunk. Additionally, generalized hirsutism was present in the whole body. Cytogenetic findings revealed an abnormality in the structural chromosome. CONCLUSION: This is the first BS case that has been reported in Iranian female population.

Serum level of anti-mullerian hormone in early follicular phase as a predictor of ovarian reserve and pregnancy outcome in assisted reproductive technology cycles.

BACKGROUND: Anti-Mullerian hormone is produced by the granulosa cells of preantral and small antral follicles. The objective of this study was to investigate whether anti-Mullerian hormone and antral follicle count can be useful in predicting the ovarian reserve and pregnancy outcome in assisted reproductive technology cycles. METHODS: This prospective study included a total of 60 patients attending an assisted reproductive technology program. Patients with an oocyte count of >or=4 were considered good responders (group A); those with <4 oocytes were considered as poor responders (group B). On day three of the menstrual cycle, blood sample was taken from each woman for the measurement of serum levels of FSH, LH, E2, and anti-Mullerian hormone. Thereafter, ovarian ultrasound scanning was performed to evaluate the number and size of antral follicles. RESULTS: Parameters such as serum FSH, LH, and E2 levels were not statistically different between the two groups. Meanwhile, the difference between serum anti-Mullerian hormone levels, AFC, HCG day follicle counts, and retrieved oocyte counts were statistically significant in the two groups. The mean+/-SD serum anti-Mullerian hormone level was 34.22+/-13.95 and 12.53+/-9.4 pM/mL in groups A and B, respectively (P=0.002). The number of chemical pregnancies was seven versus three in groups A and B, respectively (P=0.014), whereas the number of clinical pregnancies was six versus two in groups A and B, respectively (P =0.52). CONCLUSION: It appears that there is an association between the serum level of anti-Mullerian hormone in early follicular phase and ovarian reserve. Furthermore, a higher serum level of anti-Mullerian hormone on day three is associated with chemical pregnancy success.

Targeted Next-Generation Sequencing of a Deafness Gene Panel (MiamiOtoGenes) Analysis in Families Unsuitable for Linkage Analysis.

Hearing loss (HL) is a common sensory disorder in humans with high genetic heterogeneity. To date, over 145 loci have been identified to cause nonsyndromic deafness. Furthermore, there are countless families unsuitable for the conventional linkage analysis. In the present study, we used a custom capture panel (MiamiOtoGenes) to target sequence 180 deafness-associated genes in 5 GJB2 negative deaf probands with autosomal recessive nonsyndromic HL from Iran. In these 5 families, we detected one reported and six novel mutations in 5 different deafness autosomal recessive (DFNB) genes (TRIOBP, LHFPL5, CDH23, PCDH15, and MYO7A). The custom capture panel in our study provided an efficient and comprehensive diagnosis for known deafness genes in small families.

Pattern of menarche age (normal, early and late) and its relationship with some demographic characteristics in girls and their parents.

BACKGROUND: Menarche age is an indicator of a girl's puberty besides the clinical assessment of detecting deviations. This study aimed to search the pattern of menarche age (normal, early and late) and its relationship with some demographic characteristics in girls and their parents. METHODS: This cross-sectional study was done on girls aged between 9 and 18 years old in Shiraz city. About 2000 students were selected through cluster sampling. Data collection was done by applying a demographic information form. Finally, the data were analyzed using SPSS software. RESULTS: About 1386 students (69.3%) had the history of menarche (at least once). The mean age of menarche was 12.26±1.11 years in Shiraz. The menarche age of the girls ranged from 9 years (as the least) to 15 (as the maximum). The prevalence of late menarche was 1.1%. In addition, no early menarche was reported. There was no relationship between menarche age and economic status, birth order and number of children, but a significant relationship was found between the parents' education, house status, and the lifestyle of parents. CONCLUSION: The mean menarche age has been decreasing in cities. Therefore, it seems necessary for the families to be aware about the influence of time, trend and affecting factors on menarche; this helps them to make good decisions when educating their teenagers.

Deletions of exons with regulatory activity at the DYNC1I1 locus are associated with split-hand/split-foot malformation: array CGH screening of 134 unrelated families.

BACKGROUND: A growing number of non-coding regulatory mutations are being identified in congenital disease. Very recently also some exons of protein coding genes have been identified to act as tissue specific enhancer elements and were therefore termed exonic enhancers or "eExons". METHODS: We screened a cohort of 134 unrelated families with split-hand/split-foot malformation (SHFM) with high resolution array CGH for CNVs with regulatory potential. RESULTS: In three families with an autosomal dominant non-syndromic SHFM phenotype we detected microdeletions encompassing the exonic enhancer (eExons) 15 and 17 of DYNC1I1. In a fourth family, who had hearing loss in addition to SHFM, we found a larger deletion of 510 kb including the eExons of DYNC1I1 and, in addition, the human brain enhancer hs1642. Exons 15 and 17 of DYNC1I1 are known to act as tissue specific limb enhancers of DLX5/6, two genes that have been shown to be associated with SHFM in mice. In our cohort of 134 unrelated families with SHFM, deletions of the eExons of DYNC1I1 account for approximately 3% of the cases, while 17p13.3 duplications were identified in 13% of the families, 10q24 duplications in 12%, and TP63 mutations were detected in 4%. CONCLUSIONS: We reduce the minimal critical region for SHFM1 to 78 kb. Hearing loss, however, appears to be associated with deletions of a more telomeric region encompassing the brain enhancer element hs1642. Thus, SHFM1 as well as hearing loss at the same locus are caused by deletion of regulatory elements. Deletions of the exons with regulatory potential of DYNC1I1 are an example of the emerging role of exonic enhancer elements and their implications in congenital malformation syndromes.