Consanguinity in northwest Pakistan: evidence of temporal decline.

Pakistan has a high burden of hereditary and congenital anomalies and their incidence rate almost doubles against the background of parental consanguinity. Consanguineous unions (CU) are customary in Pakistan and deeply rooted socio-cultural norms favour CU. This study aimed to elucidate the determinants and temporal change in CU in four northwestern populations of Pakistan. In a cross-sectional study, data on marital union types, bio-demographic factors, and paternal consanguinity were collected from 6,323 ever-married individuals in four districts of northwest Pakistan: Haripur, Muzaffarabad, Mansehra, and Shangla. We used descriptive statistics and multivariable logistic regression analysis. The CU were calculated to be 55%, and inbreeding coefficient F (ICF) was estimated to be 0.029. Eight factors, including district, rural origin, age of husband, occupational group of husband, literacy of husband, parental consanguinity, exchange marriage, and extended family type, were found to be significant predictors of consanguinity in the multivariable logistic regression analysis. The rate of consanguinity decreased significantly in the younger age categories of individuals. The rate of CU was seen to be declining over time and in marriages that started 'before 1980' and 'after 2010', respectively, and there was a decline in ICF from 0.030 to 0.027. These analyses also showed that the literacy rate improved, the average age at marriage increased, and the frequency of exchange marriages decreased over time. This study employs a sizable first-hand dataset to demonstrate a lowering CU rate in northwest Pakistan. It is anticipated that the burden of inherited and congenital anomalies may likely to diminish in the study populations along with the fall in ICF.

Comparative Analysis of Physical and Chemical Mutagenesis in Chrysanthemum cv. 'Candid': Assessing Genetic Variation and Breeding Potential.

In this study, we developed a mutagenesis protocol specifically designed for chrysanthemum cv. "Candid" in order to introduce genetic variation. By subjecting chrysanthemum shoots to different doses of physical and chemical mutagens, we successfully generated a total of 24 mutants, each with unique genetic compositions. We observed that the mortality rate was lowest when the shoots were exposed to 10 Gy gamma irradiation and 1.00% EMS. To assess the diversity and relatedness among the mutants, we employed RAPD and SSR markers. The combination of these markers allowed us to construct a dendrogram that effectively categorized the mutant population into distinct clusters based on the specific mutagen treatments. Interestingly, the mutants induced by 10 Gy gamma irradiation exhibited greater genetic diversity in terms of flower colors. On the other hand, mutants created with 1.00% EMS displayed a higher level of variation and yielded more viable mutants. To determine the optimal markers for studying genetic diversity, we analyzed the polymorphic information content (PIC) of different markers. Among the tested markers, OPA-07 (RAPD) and JH47 (SSR) showed the highest PIC values, indicating their effectiveness in capturing genetic variability within the mutant population. Conversely, the PIC values of OPD-07 and JH20 demonstrated the lowest among the markers tested. Our results revealed a percentage of polymorphism ranging from 81.81% to 100% for RAPD markers and 66.66% to 100% for SSR markers. These findings indicate that physical mutation induced by 10 Gy gamma irradiation can be clearly distinguished from chemical mutation induced by EMS at concentrations of 1% and 0.75% in chrysanthemum cv. "Candid.″ Overall, this study provides valuable insights into the genetic composition of the generated mutants and highlights their potential for enhancing chrysanthemum-breeding programs. The identified markers, particularly, OPA-07 and JH47, can serve as valuable tools for future studies aimed at exploring and exploiting the genetic diversity within the chrysanthemum population.

Clinical and genetic attributes of congenital anomalies ascertained at a tertiary care hospital in Rawalpindi, Pakistan.

Objective: Congenital anomalies (CA) or birth defects cause substantial healthcare burden in developing countries. There are few studies from Pakistan on the prevalence-pattern of CA. The purpose of this study was to determine the prevalence-pattern and genetic attributes of CA at a tertiary care facility in Rawalpindi, Pakistan. Methods: In a cross-sectional study design, patients with CA were ascertained from Pediatric and Neonatal Section of Holy Family Hospital, Rawalpindi from March-2022 to June-2022. International Classification of Diseases (ICD-10) and Online Mendelian Inheritance in Man (OMIM) databases were utilized for uniformity in classification. The pattern of CA as well as familial/sporadic nature, syndromic/isolated presentations, and prenatal consanguinity were estimated. Descriptive summaries were generated. Results: A total of 517 independent cases with certain types of CA were recruited. There were eight major and 70 minor categories. Among the major categories, neurological disorders (39.1%) were predominating followed by neuromuscular disorders (21.1%), limb defects (13.5%), musculoskeletal defects (7.4%), blood disorders (4.3%), orofacial defects (3.9%), metabolic disorders (3.7%), and Others (7.1%). The sporadic cases were in majority (72.5%) compared to familial cases (27.5%). Further, 63% patients had syndromic presentations and there were 37% cases with isolated appearances. A total of 70% cases had parental consanguinity. Conclusion: The majority of anomalies were of preventable nature and certain healthcare measures including antinatal care and counseling can be adopted to minimize their burden. Additionally, there is an urgent need to raise awareness of the negative consequences of consanguineous marriages, which constitute a significant risk factor in cases with inherited CA.

Expanding OBSL1 Mutation Phenotype: Disproportionate Short Stature, Barrel Chest, Thoracic Kyphoscoliosis, Hypogonadism, and Hypospadias.

We present a Pakistani kinship afflicted with a syndrome with features including short stature, reduced sitting height, orofacial symptoms including prominent forehead and thick eyebrows, short and broad thorax, and variable features such as long philtrum, short broad neck, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Phenotypic variation even within different sibships was considerable. The unique combination of the phenotypic characteristics prompted us to determine the shared homozygosity regions in patient genomes and the pathogenic variants by next generation technologies like single nucleotide polymorphism (SNP) genotyping and whole exome sequencing (WES). Through these analyses, we detected homozygous OBSL1 c.848delG (p.Gly283AlafsTer54) as the causal variant. Biallelic variants in OBSL1 are known to cause Three M Syndrome 2 (3M2), a rare disorder of growth retardation with characteristic facial dysmorphism and musculoskeletal abnormalities. Affected members of the family do not have the 3M2 hallmark features of dolichocephaly, hypoplastic midface, anteverted nares, low nasal bridge, pectus excavatum, sacral hyperlordosis, spina bifida occulta, anterior wedging of thoracic vertebrae, prominent heels, and prominent talus. Moreover, they have some variable features not typical for the syndrome such as round face, disproportionate short stature, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Our study facilitated genetic diagnosis in the family, expanded the clinical phenotype for 3M2, and unraveled the considerable clinical variation within the same kinship. We conclude that unbiased molecular analyses such as WES should be more integrated into healthcare, particularly in populations with high parental consanguinity, given the potential of such analyses to facilitate diagnosis.

A Recurrent Mutation in Growth Hormone Receptor (GHR) Gene Underlying Laron-type Dwarfism in a Pakistani Family.

Laron syndrome (LS) is a rare autosomal recessively segregating disorder of severe short stature. The condition is characterized by short limbs, delayed puberty, hypoglycemia in infancy, and obesity. Mutations in growth hormone receptor (GHR) have been implicated in LS; hence, it is also known as growth hormone insensitivity syndrome (MIM-262500). Here we represent a consanguineous Pakistani family in which three siblings were afflicted with LS. Patients had rather similar phenotypic presentations marked with short stature, delayed bone age, limited extension of elbows, truncal obesity, delayed puberty, childish appearance, and frontal bossing. They also had additional features such as hypo-muscularity, early fatigue, large ears, widely-spaced breasts, and attention deficit behavior, which are rarely reported in LS. The unusual combination of the features hindered a straightforward diagnosis and prompted us to first detect the regions of shared homozygosity and subsequently the disease-causing variant by next generation technologies, like SNP genotyping and exome sequencing. A homozygous pathogenic variant c.508G>C (p.(Asp170His)) in GHR was detected. The variant is known to be implicated in LS, supporting the molecular diagnosis of LS. Also, we present detailed clinical, hematological, and hormonal profiling of the siblings.

Homozygous Mutations in Thyroid Peroxidase (TPO) in Hypothyroidism with Intellectual Disability, Developmental Delay, and Hearing and Ocular Anomalies in Two Families: Severe Manifestation of Untreated TPO-deficiency Poses a Diagnostic Dilemma.

Intellectual disability (ID) involves compromised intellectual, learning and cognitive skills, and behavioral capabilities with reduced psychomotor skills. One of the preventable causes of ID is congenital hypothyroidism (CH), which may be due to biallelic mutations in thyroid peroxidase (TPO). In low- and middle-income countries with no newborn screening programs, CH poses a great risk of ID and long-term morbidity. We report two large Pakistani families with a total of 16 patients afflicted with CH. Detailed clinical and behavioral assessments, SNP-based homozygosity mapping, linkage analysis, and exome sequencing were performed. Initially, affected individuals were referred as suffering ID (in 11 of 16 patients) and developmental delay (in 14). Secondary/associated features were verbal apraxia (in 13), goiter (in 12), short stature (in 11), limb hypotonia (in 14), no pubertal onset (five of 10 of age ≥14 years), high myopia (in eight), muscle cramps (in six), and in some, variable microcephaly and enuresis/encopresis, fits, chronic fatigue, and other behavioral symptoms, which are not characteristics of CH. Molecular genetic analyses led to the discovery of homozygous variants in TPO: novel missense variant c.719A>G (p.Asp240Gly) in family 1 and rare c.2315A>G (p.Tyr772Cys) in family 2. In low-resource countries where neonatal screening programs do not include a CH test, the burden of neurodevelopmental disorders is likely to be increased due to untreated CH. Secondly, in the background of the high prevalence of recessive disorders due to high parental consanguinity, the severe manifestation of TPO-deficiency mimics a wide range of neurological and other presentations posing a diagnostic dilemma.

A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family.

Spondylocarpotarsal synostosis (SCT) syndrome is a very rare and severe form of skeletal dysplasia. The hallmark features of SCT are disproportionate short stature, scoliosis, fusion of carpal and tarsal bones, and clubfoot. Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Homozygous variants in FLNB are known to cause SCT. This study was aimed to investigate the phenotypic and genetic basis of unique presentation of SCT syndrome segregating in a consanguineous Pakistani family. Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula. The subjects had difficulty in walking and gait problems and complained of knee pain and backache. Roentgenographic examination of the eldest patient revealed gross anomalies in the axial skeleton including thoracolumbar and cervical fusion of ribs, severe kyphoscoliosis, thoracic and lumbar lordosis, coxa valga, fusion of certain carpals and tarsals, and clinodactyly. The patients had normal faces and lacked other typical features of SCT like cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Whole exome sequencing (WES) of two affected siblings led to the discovery of a rare stop-gain variant c.220C>T (p.(Gln74*)) in exon 1 of the FLNB gene. The variant was homozygous and segregated with the malformation in this family. This study reports extensive phenotypic variability in SCT and expands the mutation spectrum of FLNB.

Incarcerated Gravid Uterus In Ventral Hernia.

Incarcerated gravid uterus for in ventral hernia is an extremely rare obstetrical and surgical problem which contributes to pregnancy related complications. We searched for literature to identify aetiology, presentation, complications, and management options for incarcerated gravid uterus, and are presenting this case with literature review. This extremely rare case report, first ever from Pakistan, of an incisional hernia containing gravid uterus as its contents and is bulging out of abdominal cavity. She presented at 27 weeks with ulceration of ventral hernia skin. She was offered a conservative treatment keeping in view maternal and foetal monitoring until term. A full-term elective lower segment caesarean section (LSCS) followed by open mesh repair was done. A successful outcome was observed. There are limited treatment options for uterine incarceration into ventral hernia, but definitive diagnosis allows procedures to treat and to reduce severe maternal and foetal complications. There is no consensus over the management of this rare condition. A tailor approach should be opted in each case. If uncomplicated, a conservative approach until term followed by delivery or LSCS and hernioplasty is a good option.

Prevalence pattern, phenotypic manifestation, and descriptive genetics of congenital limb deficiencies in Pakistan.

BACKGROUND: Congenital limb deficiency (CLD) is a group of very rare disorders characterized by substantial hypoplasia or the complete absence of 1 or more bones of limbs. Congenital limb deficiency has a significant physical, clinical, and psychological burden on the affected individuals and their families. This cross-sectional study aimed to describe the prevalence pattern, phenotypic manifestations, and biodemographic factors associated with CLD in a cohort assembled from the Pakistani population from the Northwestern region. METHODS: Through a prospective cross-sectional study, 141 individuals having 166 limbs with CLD were recruited during 2017-2021. RESULTS: There were 77 (55%) individuals with transverse defects, 61 (43%) with longitudinal defects, and 3 (2%) with Intercalary defects. Among the patients with transverse defects, 52 had terminal amputations and 25 had symbrachydactyly. Among the longitudinal defects, thumb aplasia/hypoplasia was the most common presentation (20 patients), followed by oligodactyly (18), and radial hemimelia (18). Eighty six percent had upper-limb deficiencies, 83% had unilateral deficiencies, and 92% were sporadic in nature. The parental consanguinity was observed in 33% individuals, and 79% cases had an isolated presentation which may be indicative of the substantial role of nongenetic factors in the etiology of CLD. CONCLUSIONS: This study demonstrates marked heterogeneity in CLD subtypes in the involvement of limbs and associated variables. There is a need to establish a national registry for CLD, molecular genetic diagnosis, and multidisciplinary medical and social rehabilitation services for these individuals.

Impact of interpregnancy intervals on perinatal and neonatal outcomes in a multiethnic Pakistani population.

BACKGROUND: Short birth intervals (SBIs) and long birth intervals (LBIs) have been shown to have serious implications for health of both mothers and their children. This study was aimed to investigate the determinants and reproductive outcome of SBI and LBI in a multiethnic Pakistani population. METHODS: In a cross-sectional prospective study design, 2798 women admitted in a tertiary-care hospital in Islamabad for delivery were recruited and data on second or higher birth order deliveries were collected. Birth intervals were defined as short (<24 months) and long (>36 months). The reproductive outcome was defined in terms of perinatal and neonatal mortalities, and neonatal complications. Univariate and multivariate logistic regression analyses were performed. RESULTS: Pregnancies with SBI and LBI were observed in 20% and 24% of 2798 women, respectively. Women with SBI had increased odds of perinatal death [adjusted odd ratio (AOR): 1.50] and neonatal death (AOR: 1.47) as compared to women with optimal birth intervals, while women with LBI had slightly lower odds of perinatal deaths (AOR: 0.96), but increased odds of neonatal deaths (AOR: 1.12). Further, the pregnancies with both SBI and LBI were associated with increased odds of short body length, low birth weight, small head circumference and low APGAR score. CONCLUSION: Nearly half of all pregnancies do not have optimal birth spacing albeit there is wide heterogeneity in the distribution of BI in various Pakistani ethnicities. Pregnancies with SBI and LBI had high risk of adverse reproductive outcome. Intervention programs for maternal and child health need to emphasize optimal birth spacing.

Birth interval (BI) or interpregnancy interval is the length of time between a birth and conception of the next pregnancy. Short birth intervals (SBIs) as well as long birth intervals (LBIs) have been shown to have serious implications for health of both mothers and their children. WHO recommendation for optimal spacing between 3 and 5 years. In this study, we aimed to investigate the effect of SBI and LBI on pregnancy outcome in the Pakistani population. A total of 2798 pregnant women admitted in a tertiary-care hospital in Islamabad for delivery were recruited and data on BI and pregnancy outcomes, i.e. perinatal and neonatal mortalities, and neonatal complications, were obtained. Results revealed that pregnancies with SBI and LBI were 20% and 24% of the total pregnancies, respectively. Women with SBI had higher likelihood of perinatal and neonatal death as compared to women with optimal birth intervals. Similarly, the women with LBI had higher likelihood of neonatal deaths. Furthermore, the pregnancies with both SBI and LBI were associated neonatal complications like short body length, low birth weight, small head circumference and low APGAR score. In conclusion, nearly half of all pregnancies do not have optimal birth spacing. Intervention programs for maternal and child health need to emphasize optimal birth spacing.

Burden of Congenital and Hereditary Anomalies in Hazara Population of Khyber Pakhtunkhwa, Pakistan.

Background and Objectives: In Pakistan, there is high incidence of congenital and hereditary anomalies (CA) which are a leading cause of infant mortality and morbidity. In order to elucidate the burden and biodemographic correlates of CA, this study was aimed to report the prevalence-pattern and phenotypic attributes of CA in the Hazara population of Khyber Pakhtunkhwa, Pakistan. Methods: In a retrospective cross-sectional study, subjects/families with CA were recruited from district hospitals and community centers. Phenotypic and descriptive data were obtained; pedigrees were analyzed and parental and biodemographic attributes were recorded. Results: A total of 1,189 independent subjects and/or families with CA were ascertained. The malformations were grouped into nine major and 95 minor categories. Neurological disorder had the highest representation (n=486; proportion=0.409; 95% CI=0.381-0.437), followed by limb defects (n=292; proportion=0.246, 95% CI=0.221-0.270), musculoskeletal defects, sensorineural/ear defects, blood disorders, eye/visual impairments, ectodermal anomalies, and congenital heart defects. In this cohort, sporadic cases were 65% and familial 35%. Parental consanguinity was significantly higher in isolated cases compared to syndromic, and in familial cases compared to sporadic. Further, speech apraxia and epilepsy were most common associations among the syndromic cases. The assessment of variables like demography, parental consanguinity, familial/sporadic nature, and pedigree structures showed conspicuous heterogeneity among the major and minor categories of CA. Conclusions: The trend of CA and high incidence of sporadic cases observed in this cohort indicate that nongenetic factors may play a significant role in their etiology which could be minimized by improving the healthcare system.

KERATIN 17-related recessive atypical pachyonychia congenita with variable hair and tooth anomalies.

We present the first pachyonychia congenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two consanguineous Pakistani families. This atypical PC is characterized by an unusual combination of pachyonychia, plantar keratoderma, folliculitis, alopecia, sparse eyebrows, dental anomalies and variable acanthosis nigricans of neck, dry skin, palmoplantar hyperhidrosis, recurrent blisters on soles and/or arms, rough sparse hair on scalp and keratosis pilaris. By exome sequencing we detected homozygous KRT17 c.281G>A (p.(Arg94His)) in affected individuals, and linkage mapping indicated a single locus. Heterozygous variants in KRT17 cause PC2 (PC-K17) with main characteristics of pachyonychia, subungual keratosis, palmoplantar keratoderma, hyperhidrosis, oral leukokeratosis and epidermal cysts, or steatocystoma multiplex, both with dominant inheritance. The causative variant has been reported in heterozygous state in a family afflicted with severe steatocystoma multiplex and in a sporadic PC2 case, and thus we also define a third phenotype related to the variant. Both exome sequencing and linkage mapping demonstrated recessive inheritance whereas Sanger sequencing indicated heterozygosity for the causal variant, reiterating caution for simple targeted sequencing for genetic testing. Testing parents for variants found in sibs could uncover recessive inheritance also in other KRT genes.

A Two-Base Pair Deletion in IQ Repeats in ASPM Underlies Microcephaly in a Pakistani Family.

Aims: Autosomal recessive primary microcephaly (MCPH) is a clinically rare and genetically highly heterogeneous developmental disorder. Biallelic variants in the abnormal spindle-like microcephaly-associated (ASPM) gene account for 40% to 68% of all MCPH cases. This study was designed to elucidate the genetic basis of MCPH in an extended family. To highlight recurrent mutations useful in implementing genetic testing programs, we further aimed to carry out a descriptive review of the reported ASPM mutations. Materials and Methods: A large inbred kindred with seven affected members was investigated, and detailed clinical and behavioral assessments were carried out. Single nucleotide polymorphism (SNP)-based homozygosity mapping and exome sequencing were performed. Results: Affected individuals had characteristic features, including small head, receding forehead, mild to moderate intellectual disability, developmental delay, short stature, apraxia, and behavioral anomalies. We mapped the disease gene locus and detected a rare frameshift deletion c.6854_6855del (p.(Leu2285GlnfsTer32)) in exon 18 of ASPM. A total of 215 mutations in ASPM have been reported in at least 453 families, nearly 50% of which are of Pakistani origin. These mutations can be classified as recurrent, founder or private in Pakistani and other populations. Conclusion: SNP-based homozygosity mapping and exome sequencing are essential in delineating the genetically distinct microcephaly types. The highlighted recurrent mutations in ASPM could be useful in implementing genetic testing programs for MCPH.

Burden of congenital and hereditary anomalies in the war-affected territory at Pakistan-Afghanistan border.

Background: Pashtun populations of Pakistan are the victim of long-lasting military combats, rendering 1.9 million inhabitants internally displaced. Studies highlighting congenital and hereditary anomalies in these populations are deficient. Objectives: To elucidate the spectrum anomalies in the north-western war-affected territories of Pakistan. Methods: A cross-sectional study was carried out from 2017 to 2019 and individuals or families with anomalies were ascertained through convenience and cluster random sampling. Phenotypic and pedigree data and information on bio-demographic variables were collected. Descriptive statistics were applied. Results: A total of 361 independent individuals or families with anomalies were recruited. The anomalies were grouped into 8 major and 72 minor entities. Among major categories, neurological disorders had the highest representation (n = 100; proportion: 0.277; 95% CI: 0.231-0.323), followed by sensorineural defects (n = 70; prop.: 0.194), limb defects (n = 60; prop.: 0.166), visual impairments (n = 55; prop.: 0.152), and musculoskeletal defects (n = 37; prop.: 0.102). Among the neurological disorders, intellectual disability had the highest occurrence (58%), whereas talipes and limb amputations were the most prominent in limb defects (22% and 20%, respectively). The anomalies had sporadic and isolated presentations most often (76% each), while parental consanguinity was observed in 34% of index cases. Conclusions: The high incidence of neurological, sensorineural, and limb defects, the preponderance of sporadic cases, and low level of parental consanguinity may indicate a potentially high contribution of nongenetic factors in the etiology of anomalies. The majority of anomalies are the cause of severe disability.

Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis.

Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.

A homozygous ROR2 variant in a family with atypical Robinow syndrome and tetramelic transverse deficiency of autopods.

We present five members of a consanguineous Pakistani kinship with the most severe familial tetramelic transverse autopod deficiency reported to date and additionally having some of the common autosomal recessive Robinow syndrome-1 (RRS1) features including short stature, short neck, severe vertebral anomalies of kyphoscoliosis, hemivertebrae, fusion of thoracic vertebrae, broad forehead, and dental crowding. We mapped the locus of this atypical RRS and detected homozygous 8-nucleotide deletion c.1353_1360del (p.(Met452Alafs*4)) in ROR2, the gene responsible for RRS1. We did not find any other variant shared by all affected individuals that could possibly act as a modifier of limb defect. Autopods are affected in RRS1, but severe autopod deficiency is not a characteristic feature. Over 30 biallelic variants dispersed throughout the gene are known in ROR2-related RS, with no genotype-phenotype correlation for specific RRS1 features. Considering together with the sporadic case homozygous for variant p.(Arg442*) and the case homozygous for p.(Arg441Thrfs*16) in a family where heterozygous members have brachydactyly type B1, we propose that homozygous truncating variants that originate at residues 441-452 can cause severe autopod reduction anomalies, suggesting some genotype-phenotype correlation for this particular phenotype.

Impedance Spectroscopy Analysis of PbSe Nanostructures Deposited by Aerosol Assisted Chemical Vapor Deposition Approach.

This research endeavor aimed to synthesize the lead (II) diphenyldiselenophosphinate complex and its use to obtain lead selenide nanostructured depositions and further the impedance spectroscopic analysis of these obtained PbSe nanostructures, to determine their roles in the electronics industry. The aerosol-assisted chemical vapor deposition technique was used to provide lead selenide deposition by decomposition of the complex at different temperatures using the glass substrates. The obtained films were revealed to be a pure cubic phase PbSe, as confirmed by X-ray diffraction analysis. SEM and TEM micrographs demonstrated three-dimensionally grown interlocked or aggregated nanocubes of the obtained PbSe. Characteristic dielectric measurements and the impedance spectroscopy analysis at room temperature were executed to evaluate PbSe properties over the frequency range of 100 Hz-5 MHz. The dielectric constant and dielectric loss gave similar trends, along with altering frequency, which was well explained by the Koops theory and Maxwell-Wagner theory. The effective short-range translational carrier hopping gave rise to an overdue remarkable increase in ac conductivity (σac) on the frequency increase. Fitting of a complex impedance plot was carried out with an equivalent circuit model (Rg Cg) (Rgb Qgb Cgb), which proved that grains, as well as grain boundaries, are responsible for the relaxation processes. The asymmetric depressed semicircle with the center lower to the impedance real axis provided a clear explanation of non-Debye dielectric behavior.

Prevalence-pattern and risk factors of Cesarean section in a multiethnic cohort.

OBJECTIVE: This study was aimed to elucidate the prevalence-pattern and determinant of cesarean section (CS) in a multiethnic cohort from Pakistan. METHODS: Through a cross-sectional study design, women delivering at a tertiary care center were recruited during 2013-2017. Data on socio-demographic variables, obstetric complications and birth outcome were obtained. Descriptive statistics, bivariate and multivariate logistic regression analyses were performed. RESULTS: A total of 5,275 pregnant women were recruited and 43% of the deliveries underwent CS. Odds of CS were significantly higher in subjects originating from Azad JammuKashmir and Sindh regions, speaking Potohari and Pahari languages, women in advance ages, and those who were housewives. CS had significantly lower odds of prenatal mortality but increased odds of postnatal mortality. Obstetric factors that appeared to be significant predictors of CS were multiparity, breech position, fetal distress, oligohydroamniosis, preeclampsia, and previous scar. CONCLUSION: This study revealed high variability in CS in various socio-demographic strata of study population. The obstetric complications highlighted in this study may be reduced by proper perinatal counseling and pregnancy monitoring and should be the focus of intervention programs as suggested in the Millennium Development Goals.

Consanguinity, inbreeding coefficient, fertility and birth-outcome in population of Okara district, Pakistan.

OBJECTIVES: This study was aimed to illustrate the determents of consanguinity and inbreeding coefficient-F (ICF) in the population of Okara district of Pakistan and to elucidate the impact of consanguinity on fertility and birth outcome. METHODS: Through a cross-sectional sampling design, 1,521 married women were recruited from Okara district during 2016-2017. Data on demographic variables, marital union types, subject's fertility, and reproductive outcome, were gathered in face-to-face interviews. Descriptive statistics and multivariable logistic regression were employed. RESULTS: The prevalence of consanguineous unions (CU) was calculated to be 61% yielding ICF=0.0356. Multivariable regression analyses revealed that six variables including younger age at marriage, joint family structure, caste-system of spouse, exchange marriage, matrimonial distance, and parental consanguinity, were significant predictors of consanguinity. The women having CU had significantly higher mean fertility, mean live-births and mean live-born sons compared with subjects having non-consanguineous unions (NCU). However, there were no significant differences in the average mortalities, i.e., prenatal, postnatal and <5 years, between the mothers with CU and NCU. CONCLUSION: The prevalence of consanguineous unions (CU) in Okara district is quite high like other inbred populations of Pakistan. The striking findings of this study are the higher mean fertility and mean live-births in women with CU. The likely reasons underlying this phenomenon have been discussed.