Cause Of Phenotypic Variability Research Articles

Clinical and molecular cytogenetic findings of cat eye syndrome and a 2-year-old patient with congenital aural atresia and hearing loss

BackgroundCat eye syndrome (CES) is a rare congenital disease frequently caused by a partial tetrasomy of the proximal long (q) arm of chromosome 22, due to a small supernumerary marker chromosome (sSMC). CES patients show remarkable phenotypic variability. Despite the progress of molecular cytogenetic technology, the cause of phenotypic variability and the genotype–phenotype correlations remain unknown.MethodsWe analyzed clinical and genetic data of a new patient with CES together with 27 previously reported ones with a confirmed genomic gain in the PubMed database between 2012 and 2023.ResultsWe reported a boy with CES carrying a 22q11.1-q11.21 duplication of 1.76 Mb tetrasomy (16888900_18644241, hg19) who presented currently rare or unreported clinical findings such as congenital aural atresia, hearing loss, PLSVC, and IVC. The results of the whole exome sequencing (WES) showed a heterozygous mutation of the GJB2 gene (NM_004004.6: exon2: c.109G > A). In addition, the results of our literature review showed that the presence of a classical sSMC was the most frequent cytogenetic abnormality in CES (82%). 63% of cases were in a homogenous state and 37% of cases were in a mosaic state. 72% of cases had a 1–2 Mb duplication. In the majority of CES patients the breakpoints in chromosome 22 are localized to a 50 kb region (18610000_18660000 bp). The CES critical region (CESCR) may be further delimited to a 0.3 Mb region (17799398_18111588 bp). Within this region CECR2, SLC25A18, ATP6V1E1, and BCL2L13 are strong candidate genes for causing the main CES phenotype. The ear anomalies are the most frequent features in CES patients (89%) and hearing loss was present in 36% of CES patients.ConclusionsThe phenotypic features in CES are highly variable. Our findings expand the symptom spectrum of CES and lay the foundation for better delineating the clinical phenotype, molecular cytogenetic features associated with CES and genotype–phenotype correlations. We recommend performing WES to rule out the involvement of other genetic factors in the patient’s phenotype. In addition, our findings also highlight the need for genetic counseling and recurrence risk assessment.

Phenotypic Variability and Resource Allocation in Kashmir Sage (Phlomis cashmeriana Royle ex Benth.) in relation to Different Habitats and Altitudes

Phlomis cashmeriana Royle ex Benth. commonly known as Kashmir sage is a rare and important medicinal plant growing in Kashmir Himalaya. The current study is the first of its kind, carried out to find the impingement on growth dynamics of the plant under study along various altitudinal inclines and habitats. Extensive field surveys were conducted during the years 2020-2021 to assess the distribution and phenotypic attributes of Phlomis cashmeriana. Three natural sites viz, Jawahar tunnel, Hillar naar, Daksum and one control population at KUBG were selected for the present work. Morphological characteristics of species were noticed to be varying extensively under different scopes of environment. Plants thriving at lower altitudes (KUBG) were found to be growing vigorously and taller. However, the opposite scenario was observed in plants growing at higher altitudes (Jawahar tunnel). KUBG and Daksum were reasonably found to be better habitats for the growth of Phlomis cashmeriana as revealed by principal component analysis (PCA). Majority of resources were attributed towards the growth of rhizomes followed by leaf, stem, and inflorescences respectively. Variation in reproductive success was also observed along different altitudes ranging from 63.94 % to 53.40 %. The total resource budget per plant also varied among different populations with a maximum in populations growing at low altitude, KUBG (23.73±6.63) and least in populations growing at high altitude J. tunnel (12.94±7.67). We hypothesize that a heterogeneous environment is the primary cause of phenotypic variability across different altitudes, however, the role of other environmental factors should also be taken into consideration.

Phenotypic variability and modifier variants in children with hereditary heart diseases

Despite the recent achievements in searching for the causes of monogenic human diseases, there is still a massive gap in understanding the molecular causes of phenotypic variability. At the moment, it is evident that the pathogenic genetic variant often acts together with the other genetic and non-genetic factors that can reduce or, on the contrary, aggravate the severity of the disease. Thus, to completely understand the disease, we shall consider the entire set of mechanisms leading to the resulting phenotype. This paper reviews the current state of the art in identifying genetic and non-genetic phenotype modifiers for rare monogenic cardiovascular diseases.

Causes of Phenotypic Variability and Disabilities after Prenatal Viral Infections.

Prenatal viral infection can lead to a spectrum of neurodevelopmental disabilities or fetal demise. These can include microencephaly, global developmental delay, intellectual disability, refractory epilepsy, deafness, retinal defects, and cortical-visual impairment. Each of these clinical conditions can occur on a semi-quantitative to continuous spectrum, from mild to severe disease, and often as a collective of phenotypes. Such serious outcomes result from viruses’ overlapping neuropathology and hosts’ common neuronal and gene regulatory response to infections. The etiology of variability in clinical outcomes is not yet clear, but it may be related to viral, host, vector, and/or environmental risk and protective factors that likely interact in multiple ways. In this perspective of the literature, we work toward understanding the causes of phenotypic variability after prenatal viral infections by highlighting key aspects of the viral lifecycle that can affect human disease, with special attention to the 2015 Zika pandemic. Therefore, this work offers important insights into how viral infections and environmental teratogens affect the prenatal brain, toward our ultimate goal of preventing neurodevelopmental disabilities.

Cardiopulmonary phenotypic variability and discordance in Duchenne muscular dystrophy: Implications for new therapies

Neuromuscular respiratory medicine has traditionally focused on assisted lung ventilation and mucus clearance. These therapies have prolonged survival for patients with Duchenne muscular dystrophy (DMD). However, the field is rapidly evolving in a new direction: it is being revolutionized by molecular and genetic therapies. A good correlation between a patient's dystrophin mutation and his cardiopulmonary phenotype would allow accurate prediction of patient prognosis and would facilitate the design of studies that assess new DMD therapies. Instead, patient prognosis and the design of valid therapeutic studies are complicated by cardiopulmonary phenotypic discordance and variability, by which a notable proportion of DMD patients have unexpectedly good or poor cardiopulmonary function. The likely cause of phenotypic variability and discordance is genetic modifiers. Once the modifiers that affect cardiopulmonary function are better understood, it should be possible to create a personalized genetic profile that accurately predicts the prognosis of each individual DMD patient. This would allow investigators to assess the effect of new therapies in the context of each patient's particular cardiopulmonary natural history. Amplification of beneficial cardiopulmonary genetic modifiers and blocking of detrimental modifiers is a promising strategy for creating new DMD therapies. When patients with chronic respiratory failure are treated with assisted ventilation, cardiac function determines their survival. Therefore, prioritizing new cardiac therapies is most likely to prolong patient survival. By focusing on these topics we aim to move neuromuscular respiratory medicine beyond assisted ventilation and coughing and into the age of translational medicine.

CpG-SNP site methylation regulates allele-specific expression of MTHFD1 gene in type 2 diabetes

AbstractThe interaction of genetic and epigenetic mechanisms is one of the underlying causes of phenotypic variability in complex diseases such as type 2 diabetes (T2D). To explore the influence of genetic and epigenetic changes in T2D, we examined the effect of methylation of CpG-SNP sites on allele-specific expression (ASE) in one-carbon metabolism pathway genes in T2D. Case-control study was conducted on 860 individuals (430 T2D and 430 controls). CpG-SNPs shortlisted through in silico analysis were genotyped using tetra ARMS PCR and validated using Sanger DNA sequencing. Global DNA methylation was carried out using RP-HPLC. Promoter DNA methylation and CpG site-specific methylation were carried out using bisulfite sequencing. mRNA expression and ASE were examined by SYBR green and TaqMan assay, respectively. Four exonic CpG-SNPs of MTHFD1, MTRR, and GGH genes were identified in folate pathway genes. Among these, MTHFD1 rs2236225 showed significant association with T2D independent of obesity, displayed ASE, and correlated with CpG-SNP site-specific methylation when compared with controls. Our results demonstrate that SNP rs2236225 in the CpG site of MTHFD1, which regulates allele-specific gene expression in PBMCs is methylation dependent and may perturb one-carbon metabolism pathway in T2D subjects.The interaction of genetic and epigenetic mechanisms is one of the underlying causes of phenotypic variability in diseases like type 2 diabetes. The authors identified the methylation-dependent CpG-SNP in the MTHFD1 gene as a regulator of allele-specific gene expression in peripheral blood mononuclear cells, which may perturb one-carbon metabolism in diabetes.

Genomic imprinting analyses identify maternal effects as a cause of phenotypic variability in type 1 diabetes and rheumatoid arthritis

Imprinted genes, giving rise to parent-of-origin effects (POEs), have been hypothesised to affect type 1 diabetes (T1D) and rheumatoid arthritis (RA). However, maternal effects may also play a role. By using a mixed model that is able to simultaneously consider all kinds of POEs, the importance of POEs for the development of T1D and RA was investigated in a variance components analysis. The analysis was based on Swedish population-scale pedigree data. With P = 0.18 (T1D) and P = 0.26 (RA) imprinting variances were not significant. Explaining up to 19.00% (± 2.00%) and 15.00% (± 6.00%) of the phenotypic variance, the maternal environmental variance was significant for T1D (P = 1.60 × 10−24) and for RA (P = 0.02). For the first time, the existence of maternal genetic effects on RA was indicated, contributing up to 16.00% (± 3.00%) of the total variance. Environmental factors such as the social economic index, the number of offspring, birth year as well as their interactions with sex showed large effects.

Beyond quantitative and qualitative traits: three telling cases in the life sciences

This paper challenges the common assumption that some phenotypic traits are quantitative while others are qualitative. The distinction between these two kinds of traits is widely influential in biological and biomedical research as well as in scientific education and communication. This is probably due to both historical and epistemological reasons. However, the quantitative/qualitative distinction involves a variety of simplifications on the genetic causes of phenotypic variability and on the development of complex traits. Here, I examine three cases from the life sciences that show inconsistencies in the distinction: Mendelian traits (dwarfism and pigmentation in plant and animal models), Mendelian diseases (phenylketonuria), and polygenic mental disorders (schizophrenia). I show that these traits can be framed both quantitatively and qualitatively depending, for instance, on the methods through which they are investigated and on specific epistemic purposes (e.g., clinical diagnosis versus causal explanation). This suggests that the received view of quantitative and qualitative traits has a limited heuristic power—limited to some local contexts or to the specific methodologies adopted. Throughout the paper, I provide directions for framing phenotypes beyond the quantitative/qualitative distinction. I conclude by pointing at the necessity of developing a principled characterisation of what phenotypic traits, in general, are.

Causal Attributions in an Australian Aboriginal Family With Marfan Syndrome: A Qualitative Study.

Causal attributions are important determinants of how health threats are processed and affect health-related behaviors. To date, there has been no research on causal attributions in genetic conditions in Aboriginal Australians. Forty members of a large Aboriginal Australian family with Marfan syndrome (MFS) were invited to participate in an ethically approved study exploring causal attributions, including perceived causes of phenotypic variability within the family. Eighteen individuals consented to conduct semi-structured qualitative interviews, which were recorded, transcribed verbatim and analyzed thematically. Most participants knew that MFS was genetic, but there were diverse theories about inheritance, including beliefs that it skipped generations, was affected by birth order and/or gender, and that it co-occurred with inheritance of blue eyes within this family. The mutation was thought to have been inherited from British settlers and initially triggered by disease or diet. Factors believed to modify disease severity included other genes and lifestyle factors, particularly alcohol and substance abuse and stress. Generally, this family did not endorse “blaming” chance or a higher power for phenotypic variability, though some felt that the spirits or a deity may have played a role. In conclusion, although participants knew MFS was a genetic condition, many speculated about the role of non-genetic causes in initiating the original mutation; and the gene-environment interaction was thought to affect severity. This study demonstrates a successful approach for exploring causal attributions in other genetic conditions in First Australians.

Whole exome sequencing of families with 1q21.1 microdeletion or microduplication

Recurrent microduplications/microdeletions of 1q21.1 are characterized by variable phenotypes ranging from normal development to developmental delay (DD) and congenital anomalies. Their interpretation is challenging especially in families with affected and unaffected carriers. We used whole exome sequencing (WES) to look for sequence variants in two male probands with inherited 1q21.1 CNVs that could explain their more severe phenotypes. One proband had a 1q21.1 deletion transmitted from maternal grandmother, while the other had a paternal duplication. We found mutations in five genes (SMPD1, WNK3, NOS1, ATF6, and EFHC1) that could contribute to the more severe phenotype in the probands in comparison to their mildly affected or unaffected 1q21.1 CNV carrying relatives. Interestingly, all genes have roles in stress responses (oxidative/Endoplasmic Reticulum (ER)/osmotic). One of the variants was in an X-linked gene WNK3 and segregated with the developmental features and X inactivation pattern in the family with 1q21.1 deletion transmitted from maternal grandmother. In silico analysis of all rare deleterious variants in both probands identified enrichment in nervous system diseases, metabolic pathways, protein processing in the ER and protein export. Our studies suggest that rare deleterious variants outside of the 1q21.1 CNV, individually or as a pool, could contribute to phenotypic variability in carriers of this CNV. Rare deleterious variants in stress response genes are of interest and raise the possibility of susceptibility of carriers to variable environmental influences. Next generation sequencing of additional familial cases with 1q21.1 CNV could further help determine the possible causes of phenotypic variability in carriers of this CNV.

Rescuable folding defective NaV1.1 (SCN1A) mutants in epilepsy: Properties, occurrence, and novel rescuing strategy with peptides targeted to the endoplasmic reticulum

Mutations of the voltage gated Na+ channel NaV1.1 (SCN1A) are important causes of different genetic epilepsies and can also cause familial hemiplegic migraine (FHM-III). In previous studies, some rescuable epileptogenic folding defective mutants located in domain IV of NaV1.1 have been identified, showing partial loss of function also with maximal rescue. Variable rescue may be one of the causes of phenotypic variability, and rescue might be exploited for therapeutic approaches. Recently, we have identified a folding defective FHM-III NaV1.1 mutant that showed overall gain of function when rescued, consistent with a differential pathomechanism.Here, we have evaluated functional properties and cell surface expression of six NaV1.1 epileptogenic missense mutations in different rescuing conditions, including a novel one that we have developed expressing a selective sodium channel toxin (CsEI) targeted to the endoplasmic reticulum (ER). All the mutants showed loss of function and reduced cell surface expression, consistently with possibility of rescue. Four of them were rescuable by incubation at low temperature and interactions with different co-expressed proteins or a pharmacological chaperone (phenytoin). Notably, CsEI was able to rescue four mutants. Thus, NaV1.1 folding defective mutants can be relatively common and mutations inducing rescuable folding defects are spread in all NaV1.1 domains. Importantly, epileptogenic mutants showed overall loss of function even upon rescue, differently than FHM-III ones. The effectiveness of CsEI demonstrates that interactions in the ER are sufficient for inducing rescue, and provides a proof of concept for developing possible therapeutic approaches that may overcome some limitations of pharmacological chaperones.

Ring 18 molecular assessment and clinical consequences

Ring chromosome 18 is a rare condition which has predominantly been described by case reports and small case series. We assessed a cohort of 30 individuals with ring 18 using both microarray comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). We determined that each participant had a unique combination of hemizygosity for the p and q arms. Four ring chromosomes had no detectable deletion of one of the chromosome arms using aCGH. However, two of these ring chromosomes had telomeric sequences detected using FISH. These data confirm the importance of molecular and cytogenetic analysis to determine both chromosome content and morphology. We failed to find dramatic changes in mosaicism percentage between cytogenetic measurements made at the time of diagnosis and those made years later at the time of this study, demonstrating that dynamic ring mosaicism is unlikely to be a major cause of phenotypic variability in the ring 18 population. Lastly, we present data on the clinical features present in our cohort, though the extreme genotypic variability makes it impossible to draw direct genotype-phenotype correlations. Future work will focus on determining the role of specific hemizygous genes in order to create individualized projections of the effect of each person's specific ring 18 compliment.

Detection of somatic and germline mosaicism for the LAMP2 gene mutation c.808dupG in a Chinese family with Danon disease

Danon disease is a rare X-linked lysosomal storage disease characterized by hypertrophic cardiomyopathy, myopathy and mental retardation, and is due to a primary defect in lysosome-associated membrane protein-2 (LAMP 2). More than 26 mutations in the LAMP2 gene have been described, including a small number of de novo mutations, some of which are suspected to be caused by germline mosaicism. Here, we describe the first molecularly documented evidence of somatic mosaicism for a LAMP2 mutation, identified in the asymptomatic mother of a boy with Danon disease caused by the frameshift mutation c.808dupG (p.A270Gfx3) within exon 6. In addition, in order to gain insight into the possible explanation for the mother's lack of phenotype, the level of somatic mosaicism and the X-chromosome inactivation pattern were investigated. This study provides new insight into the causes of phenotypic variability in female mutation-carriers and underlines the importance of parental molecular testing for accurate genetic counseling for Danon disease.

015 Identifying the cause of phenotypic variability in a family with non-dystrophic myotonia

Non-dystrophic Myotonia (NDM) is the commonest group of skeletal muscle channelopathies often causing severe myotonia in patients. It is either caused by mutations in the skeletal muscle chloride channel gene,...

Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs

To report a new phenotype with additional data on the oculo-dental syndrome of cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) caused by mutations on CNNM4, a metal transporter, with linkage at achromatopsia locus 2q11 (Jalili syndrome). Three siblings aged 5, 6, and 10 years from a six-generation Arab family in Gaza City underwent full systemic, ophthalmic, and dental examinations, investigations and detailed genealogy. Subjects presented at early childhood with visual impairment and abnormal dentition together with photophobia and fine nystagmus increasing under photopic conditions, in the presence of normal fundi. Electrophysiologically, photopic flicker responses were impaired; scotopic responses were extinguished at the age of 10 years. Anterior open bite accompanied AI in all siblings. The syndrome formed 83% of CRD cases in the Gaza Strip, which has a prevalence of 1 : 10,000. On the basis of clinical features and electrophysiology, two phenotypes exist: an infancy onset form with progressive macular lesion and an early childhood onset form with normal fundi. More prevalent than previously thought, Jalili syndrome presents a model of the effect of different mutations of the same genetic defect, observations of the same phenotype at different stages of the natural history of the disease, and the influence of epigenetic and tissue-specific factors as causes of phenotypic variability. The paper calls for action to tackle consanguinity in endogamous communities, addresses the possible role of high fluoride levels in groundwater as a trigger for genetic mutations, and the use of red-tinted filter in cone disorders.

Delineation of 15q13.3 microdeletions

The increasing use of array-comparative genomic hybridization (array-CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4-BP5 microdeletion out of a series of 4625 patients screened by array-CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical approximately 1.5 Mb BP4-BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.

Traffic Jam at the Sodium Channel

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+ Channel Mutant. Rusconi R, Scalmani P, Cassulini RR, Giunti G, Gambardella A, Franceschetti S, Annesi G, Wanke E, Mantegazza M. J Neurosci 2007;27(41):11037–11046. Familial epilepsies are often caused by mutations of voltage-gated Na+ channels, but correlation genotype–phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Nav1.1 (SCN1A) Na+ channel subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature <30°C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na+ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein–protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.

Genetic Modification of the Schisis Phenotype in a Mouse Model of X-Linked Retinoschisis

X-linked retinoschisis (XLRS) is an inherited form of macular degeneration that is caused by mutations in the retinoschisin (RS1) gene. In addition to macular degeneration, other major characteristics of XLRS include splitting of the retina (schisis) and impaired synaptic transmission as indicated by a reduction in the electroretinogram b-wave. It has been known that patients carrying RS1 mutations show a broad range of phenotypic variability. Interestingly, phenotypic variation is observed even among family members with the same RS1 mutation, suggesting the existence of genetic or environmental factors that contribute to the severity of XLRS. However, in the human population, the cause of phenotypic variability and the contribution of genetic modifiers for this relatively rare disease are difficult to study and poorly understood. In this study, using a mouse model for XLRS, we show that genetic factors can contribute to the severity of the retinoschisis phenotype. We report evidence of a major genetic modifier of Rs1, which affects the disease severity in these animals. A quantitative trait locus (QTL), named modifier of Rs1 1 (Mor1), is mapped on chromosome (Chr) 7. When homozygous, the Mor1 allele from the inbred mouse strain AKR/J diminishes the severity of the schisis phenotype in Rs1(tmgc1)/Y male and Rs1(tmgc1)/Rs1(tmgc1) female mice. We also show that the penetrance of the disease phenotype is affected by additional genetic factor(s). Our study suggests that multiple genetic modifiers could potentially be responsible for the phenotypic variation in human XLRS.

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

Familial epilepsies are often caused by mutations of voltage-gated Na+ channels, but correlation genotype-phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na(v)1.1 (SCN1A) Na+ channel alpha subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature <30 degrees C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na+ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein-protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.