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Split-hand/foot malformation (SHFM) shows diverse heterogeneity and manifests with reduced penetrance and variable expressivity. This study investigated the underlying genetic cause of a family segregating SHFM. Exome sequencing followed by Sanger sequencing identified a novel single nucleotide heterozygous variant (NC_000019.9 (NM_005499.3):c.1118del) in UBA2 cosegregating in the family in an autosomal dominant manner. Our findings conclude that reduced penetrance and variable expressivity are the two remarkable and unusual features of SHFM.

Background: Dystrophic Epidermolysis bullosa (DEB) is a rare, severe subtype of epidermolysis bullosa (EB), characterized by blisters and miliary rashes of the skin. Dystrophic EB (DEB) includes variants inherited both in an autosomal-dominant or autosomal-recessive manner. Recessive dystrophic EB (RDEB) is divided into many subtypes and prevails as a result of biallelic genetic mutations in COL7A1 gene encoding type VII collagen, a major stabilizing molecule of the dermo-epidermal junction. The blister formation is mainly due to the variable structural and functional impairment of anchoring fibrils in VII collagen (COLVII), responsible for the adhesion of the epidermis to the dermis. Method: Three Pakistani families (A, B and C) affected with congenital dystrophic epidermolysis bullosa were recruited in the present study. The whole-exome sequencing (WES) approach was utilized for the detection of the pathogenic sequence variants in probands. The segregation of these variants in other participants was confirmed by Sanger sequencing. Results: This study identified a novel missense variant c.7034G>A, p. Gly2345Asp in exon 91, a novel Frameshift mutation c.385del (p. His129MetfsTer18) in a homozygous form in exon no 3, and a previously known nonsense variation (c.1573 C>T; p. Arg525Ter) in exon 12 of COL7A1 gene in families A, B, and C, respectively, as causative mutations responsible for dystrophic epidermolysis bullosa in these families. Conclusion: Our study validates the involvement of the COL7A1 gene in the etiology of dystrophic epidermolysis bullosa. It further expands the COL7A1 gene mutation database and provides an additional scientific basis for diagnosis, genetic counseling, and prognosis purposes for EB patients.

Aim. This research study aims to examine the professional quality of life (ProQOL) among healthcare workers (HCWs) in Pakistan during the fourth wave of COVID-19. Background. Under intense pressure to fight the coronavirus disease 2019 (COVID-19) pandemic, HCWs are more likely to experience psychological problems. Numerous investigations carried out in the past at various points during the pandemic have shown that COVID-19 has had important detrimental effects on HCWs. However, there are many unknowns with regard to ProQOL for HCWs. Methods. This is a cross-sectional study conducted with Pakistani HCWs who performed their duties during the fourth wave of COVID-19. Data were collected between January 1 and March 31, 2022. A total of 258 HCWs took part in the study evaluating ProQOL. The significance level was <0.05. Results. Most respondents were males (79.1%), and 20.9% were females. The scores of secondary traumatic stress (STS), burnout (BO), and compassion satisfaction (CS) were 24.03 ± 3.79, 19.18 ± 2.92, and 35.29 ± 4.37, respectively. Compared with higher-income groups, HCWs with lower incomes were significantly (P<0.001) more likely to experience psychological issues. Males had lower BO and STS than female HCWs (P<0.001). Similarly, doctors had a lower STS than nurses (P<0.05). HCWs who worked hours per day longer had a heavier STS (P<0.001). Conclusion. This study shows low BO levels, moderate CS levels, and STS levels among HCWs. HCWs with lower salary were at a higher risk of mental distress due to the pandemic. HCWs who worked for long hours and had less income had more STS and BO. HCWs who were dissatisfied with their works had poor CS. Implications for Nursing Management. It is supposed that these results may help HCW managers to improve job satisfaction and rewards while reducing working hours and workload to improve the ProQOL of HCWs fighting COVID-19. The government should focus on the mental health of HCWs, enhancing their satisfaction and allocating sufficient resources.

Background: Occupational stress refers to the psychological pressure from work‐related factors. Stress overload is a key contributor to the global nursing shortage. Excessive workloads and psychological pressure further exacerbate stress among healthcare professionals. Aims: This study aims to examine the impact of psychological counseling (PC), job characteristics, and perceived respect on occupational stress among Pakistani nurses. Methods: This cross‐sectional study was carried out by nurses from Pakistan, using a random sampling method. Data were collected between April 1 and May 31, 2024. We have access to the nurses’ work‐related stress, respect, and PC through an online questionnaire. A total of 292 nurses took part in the study. Results: Out of 292 participants, 276 completed the survey, with 71.38% male and 28.62% female. The main causes of occupational stress were low income (95.56%), high workload (80.80%), occupational injury (65.95%), family factors (64.50%), strict leadership (60.50%), and physical problems (56.16%). Additionally, 36.23% of nurses had limited faith in the effectiveness of PC, followed by a moderate belief. According to multiple logistic regression analyses, a correlation between a PC high work‐related stress significantly affects nurses’ mental health, increasing the need for PC ( p = 0.0979). Stress relief methods like reading, music, or outdoor sports reduce the stress (OR 2.298–11.031, p < 0.001). At the same time, factors like nurse–patient relationships and strict leadership contribute to high‐stress levels ( p = 0.417, p = 0.682), with reducing work intensity showing minimal impact ( p = 0.993). Conclusion: Our study indicated that low salaries, a high workload, and low respect could cause occupational stress among nurses who need high PC. Implications for Nursing Management: These findings can guide hospital administrators and nurse managers in enhancing rewards, reducing work hours, and improving job satisfaction. Additionally, better working conditions and training programs can help mitigate occupational stress and support nurses’ mental health.

Background: The demanding requirements of nursing education impose great stress on students, which can adversely affect their health and well‐being in terms of academic and clinical performance. Aims: This study aimed to determine the level of stress and the main causes of stress among medical and nursing students. Methods: This cross‐sectional study was conducted with medical and nursing students in Pakistan via a convenience sampling method. Sources of stress‐associated factors were assessed using online questionnaire. The data were collected between July 1 and August 31, 2024. A total of 302 medical and nursing students participated in the research. Descriptive statistics (frequency, mean) and inferential statistics were used to analyze the collected data. Results: According to the findings, medical and nursing students experience stress from multiple sources, with financial difficulties, academic workload, clinical practice, and environmental factors being the primary contributors. The most common stressors were insufficient income, pressure from clinical instructors and staff, and unfamiliarity with patient diagnoses and treatments. Multifactor logistic regression analysis revealed that stress from assignments and workload was significantly associated with fear of poor grades ( p = 0.046), while clinical practice quality also showed a significant effect ( p = 0.029). Additionally, dealing with patients with physio‐psychosocial issues ( p = 0.039) and unfamiliarity with clinical conditions ( p = 0.012) were significant predictors of stress. These findings highlight the complex and multifaceted nature of student stress. Conclusion: This study revealed that medical and nursing students experience significant levels of stress related to finances, clinical practice, and academics, which affects their performance. Medical and Nursing Implications: Educational administrators must establish policies that assist medical and nursing students. Some of these policies could include evaluating the workload of Medical and nursing students, refining curriculum design, providing financial support, and providing scholarships to students facing challenging circumstances.

Background Intellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome. Methods Exome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing. Results In an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family. Conclusions The investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Background Intellectual disability (ID) is a condition that varies widely in both its clinical presentation and its genetic underpinnings. It significantly impacts patients’ learning capacities and lowers their IQ below 70. The solute carrier (SLC) family is the most abundant class of transmembrane transporters and is responsible for the translocation of various substances across cell membranes, including nutrients, ions, metabolites, and medicines. The SLC13A3 gene encodes a plasma membrane-localized Na+/dicarboxylate cotransporter 3 (NaDC3) primarily expressed in the kidney, astrocytes, and the choroid plexus. In addition to three Na + ions, it brings four to six carbon dicarboxylates into the cytosol. Recently, it was discovered that patients with acute reversible leukoencephalopathy and a-ketoglutarate accumulation (ARLIAK) carry pathogenic mutations in the SLC13A3 gene, and the X-linked neurodevelopmental condition Christianson Syndrome is caused by mutations in the SLC9A6 gene, which encodes the recycling endosomal alkali cation/proton exchanger NHE6, also called sodium-hydrogen exchanger-6. As a result, there are severe impairments in the patient’s mental capacity, physical skills, and adaptive behavior. Methods and results Two Pakistani families (A and B) with autosomal recessive and X-linked intellectual disorders were clinically evaluated, and two novel disease-causing variants in the SLC13A3 gene (NM 022829.5) and the SLC9A6 gene (NM 001042537.2) were identified using whole exome sequencing. Family-A segregated a novel homozygous missense variant (c.1478 C > T; p. Pro493Leu) in the exon-11 of the SLC13A3 gene. At the same time, family-B segregated a novel missense variant (c.1342G > A; p.Gly448Arg) in the exon-10 of the SLC9A6 gene. By integrating computational approaches, our findings provided insights into the molecular mechanisms underlying the development of ID in individuals with SLC13A3 and SLC9A6 mutations. Conclusion We have utilized in-silico tools in the current study to examine the deleterious effects of the identified variants, which carry the potential to understand the genotype-phenotype relationships in neurodevelopmental disorders.

Background Woodhouse‐Sakati syndrome is a rare autosomal recessive disease with endocrine and neuroectodermal aberrations with heterogeneous phenotypes and disease course. The most common phenotypes of the disease are progressive sensorineural hearing loss and alopecia, mild‐to‐moderate mental retardation and hypogonadism. The disease results from mutations in the DCAF17 gene. Method Here, we reported a large consanguineous pedigree with multiple affected individuals with Woodhouse‐Sakati syndrome phenotypes. Laboratory tests confirmed the endocrine perturbance in affected individuals. To find out the underlying genetic change, whole‐exome sequencing was carried out. Result Analysis of the exome data identified a splicing‐site deletion NM_025000.3:c.1423‐1_1425delGACA in DCAF17 gene. Sanger sequencing confirmed the co‐segregation of the variant with the disease phenotypes in the family. Conclusion The variant is predicted to cause aberrant splicing, i.e., exon skipping, resulting in the translation of a truncated functionless protein which results in appearance of typical phenotypic features and clinical laboratory findings of Woodhouse‐Sakati syndrome in affected members of the family. Woodhouse‐Sakati syndrome, a rare autosomal recessive disease with endocrine and neuroectodermal abnormalities including progressive sensorineural hearing loss, alopecia, mental retardation and hypogonadism resulting from mutations in the DCAF17 gene. Here we reported a large consanguineous family with multiple affected individuals showing Woodhouse‐Sakati syndrome phenotypes and having a novel a splice site deletion mutation in DCAF17 gene

The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypodontia/oligodontia, along with hypohidrosis/anhidrosis, and hypotrichosis. Pathogenic variants in EDA, EDAR, EDARADD, and TRAF6, cause the phenotypic expression of HED. Genetic alterations in EDA and WNT10A cause particularly non-syndromic/isolated oligodontia. In the current project, we recruited 57 patients of 17 genetic pedigrees (A-Q) from different geographic regions of the world, including Pakistan, Egypt, Saudi Arabia, and Syria. The molecular investigation of different syndromic and non-syndromic dental conditions, including hypodontia, oligodontia, generalized odontodysplasia, and dental crowding was carried out by using exome and Sanger sequencing. We have identified a novel missense variant (c.311G>A; p.Arg104His) in WNT10A in three oligodontia patients of family A, two novel sequence variants (c.207delinsTT, p.Gly70Trpfs*25 and c.1300T>G; p.Try434Gly) in EDAR in three patients of family B and four patients of family C, respectively. To better understand the structural and functional consequences of missense variants in WNT10A and EDAR on the stability of the proteins, we have performed extensive molecular dynamic (MD) simulations. We have also identified three previously reported pathogenic variants (c.1076T>C; p.Met359Thr), (c.1133C>T; p.Thr378Met) and (c.594_595insC; Gly201Argfs*39) in EDA in family D (four patients), E (two patients) and F (one patient), correspondingly. Presently, our data explain the genetic cause of 18 syndromic and non-syndromic tooth agenesis patients in six autosomal recessive and X-linked pedigrees (A-F), which expand the mutational spectrum of these unique clinical manifestations.

Bardet–Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. The primary clinical and diagnostic features include six different hallmarks, such as rod–cone dystrophy, learning difficulties, renal abnormalities, male hypogonadism, post-axial polydactyly, and obesity. Here, we report nine consanguineous families and a non-consanguineous family with several affected individuals presenting typical clinical features of BBS. In the present study, 10 BBS Pakistani families were subjected to whole exome sequencing (WES), which revealed novel/recurrent gene variants, including a homozygous nonsense mutation (c.94C>T; p.Gln32Ter) in the IFT27 (NM_006860.5) gene in family A, a homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B, a homozygous nonsense variant (c.720C>A; p.Cys240Ter) in the WDPCP (NM_015910.7) in family C, a homozygous nonsense variant (c.505A>T; p.Lys169Ter) in the LZTFL1 (NM_020347.4) in family D, pathogenic homozygous 1 bp deletion (c.775delA; p.Thr259Leufs*21) in the MKKS/BBS5 (NM_170784.3) gene in family E, a pathogenic homozygous missense variant (c.1339G>A; p.Ala447Thr) in BBS1 (NM_024649.4) in families F and G, a pathogenic homozygous donor splice site variant (c.951+1G>A; p?) in BBS1 (NM_024649.4) in family H, a pathogenic bi-allelic nonsense variant in MKKS (NM_170784.3) (c.119C>G; p.Ser40*) in family I, and homozygous pathogenic frameshift variants (c.196delA; p.Arg66Glufs*12) in BBS5 (NM_152384.3) in family J. Our findings extend the mutation and phenotypic spectrum of four different types of ciliopathies causing BBS and also support the importance of these genes in the development of multi-systemic human genetic disorders.