Wide Phenotypic Variability Research Articles

Do you know this syndrome?

Noonan Syndrome is one of the most common genetic syndromes and also an important differential diagnosis in children presenting with syndromic facies similar to Turner's syndrome phenotype. This syndrome is characterized by facial dysmorphism, congenital heart defects, short stature and also a wide phenotypic variation. This article discusses the case of a 10 year-old patient with Noonan syndrome that presented typical facies, cardiac defects (pulmonary dilatation and mitral regurgitation), dental malocclusion, micrognatism, short stature and a certain degree of learning disability.

Primary and secondary dystonic syndromes

Purpose of reviewThe dystonias are a common but complex group of disorders that show considerable variation in cause and clinical presentation. The purpose of this review is to highlight the most important discoveries and insights from across the field over the period of the past 18 months.Recent findingsFive new genes for primary dystonia (PRRT2, CIZ1, ANO3, TUBB4A and GNAL) have made their appearance in the literature. New subtypes of neuronal brain iron accumulation have been delineated and linked to mutations in C19orf12 and WDR45, while a new treatable form of dystonia with brain manganese deposition related to mutations in SLC30A10 has been described. At the same time, the phenotypes of other forms of dystonic syndromes have been expanded or linked together. Finally, there has been increasing recognition of both the extramotor phenotype in dystonia and the part played by the cerebellum in its pathophysiology.SummaryRecently, there has been unprecedented change in the scientific landscape with respect to the cause of various dystonic syndromes that is likely to make a direct impact on clinical practice in the near future. Understanding the genetic cause of these syndromes and the often wide phenotypic variation in their presentations will improve diagnosis and treatment. With time, these discoveries may also lead to much-needed progress in elucidating the underlying pathophysiology of dystonia.

Utilidad de la logopedia en la mejora del lenguaje en el tratamiento del síndrome del cromosoma X frágil en niños preescolares

Fragile X syndrome (FXS) is the most common cause-and the second genetic cause-of intellectual disability. There is wide variability in the behavioral phenotype associated with this syndrome and consequently evaluation should be individualized. We report the exhaustive initial evaluation, follow-up and achievements of two children (aged 16 and 27months) with FXS with a full mutation. One child received speech therapy, while the other did not. Children with FXS should be individually assessed to determine their specific developmental impairments. Although the literature predicts that affected individuals will show cognitive and language deficits, we found that the two children assessed in this study required interventions aimed at improving motor skills and autonomy, especially the second child.

Comparison of Two-Dimensional and Three-Dimensional Images for Phenotypic Assessment of Craniofacial Microsomia

Background and Purpose : Three-dimensional surface imaging is used in many craniofacial centers. However, few data exist to indicate whether such systems justify their cost. Craniofacial microsomia is associated with wide phenotypic variability and can affect most facial features. The purpose of this study is to compare three-dimensional versus two-dimensional images for classification of facial features in individuals with craniofacial microsomia. Methods : We obtained a series of two-dimensional and three-dimensional images of 50 participants, aged 0-20 years, diagnosed with craniofacial microsomia, microtia, or Goldenhar syndrome. Three clinicians classified the craniofacial features on each image, and ratings were compared by calculating kappa statistics. We also evaluated image quality using a 5-point Likert scale. Results : Reliability estimates were high for most features using both two-dimensional and three-dimensional image data. Our three-dimensional protocol did not allow for scoring of facial animation, occlusal cant, or tongue anomalies. Image quality scores for the mandible and soft tissue assessment were higher for three-dimensional images. Raters preferred two-dimensional photographs for assessment of the ear, ear canal, and eyes. Conclusions : Both three-dimensional and two-dimensional images provide useful data for objective characterization of the craniofacial features affected in craniofacial microsomia. A series of two-dimensional images has relative advantages for assessment of some specific features, such as the ear, though three-dimensional images may have advantages for quantitative analysis and qualitative assessment of deformities of the jaw and soft tissue. These results should apply to any assessment of these features with or without a craniofacial microsomia diagnosis.

Modulatory effect of BclI GR gene polymorphisms on the obesity phenotype in Brazilian patients with Cushing's disease

OBJECTIVES:Patients with Cushing's disease exhibit wide phenotypic variability in the severity of obesity, diabetes and hypertension. In the general population, several glucocorticoid receptor genes (NR3C1) and HSD11B1 polymorphisms are associated with altered glucocorticoid sensitivity and/or metabolism, resulting in an increased or reduced risk of an adverse metabolic profile. Our aim was to analyze the association of NR3C1 and HSD11B1 gene variants with the severity of some clinical and hormonal features of Cushing's disease.METHODS:Sixty-four patients presenting with Cushing's disease were diagnosed based on adrenocorticotrophic hormone levels, high-dose dexamethasone suppression tests and/or inferior petrosal sinus sampling and magnetic resonance imaging. The A3669G, ER22/23EK, N363S BclI-NR3C1 and HSD11B1-rs12086634 variants were screened.RESULTS:The BclI, HSD11B1-rs12086634 and A3669G variants were found in 36%, 19.5% and 14% of alleles, respectively. The N363S and ER22/23EK polymorphisms were identified in heterozygosis once in only two patients (1.5% of alleles). There were no differences in the weight gain or prevalence of diabetes and hypertension in the patients carrying the abovementioned alleles compared to the wild-type carriers. Interestingly, the mean body mass index (BMI) of the BclI carriers was significantly higher than the non-carriers (34.4±7 kg/m2 vs. 29.6±4.7 kg/m2, respectively). None of the polymorphisms were associated with the basal adrenocorticotrophic hormone, FU levels or F level after dexamethasone suppression testing.CONCLUSION:Although Cushing's disease results from increased glucocorticoid secretion, we observed that interindividual variability in the peripheral glucocorticoid sensitivity, mediated by the glucocorticoid receptor, could modulate the obesity phenotype.

NCL diseases — clinical perspectives

The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage disorders and together are the most common degenerative brain diseases in childhood. They are a group of disorders linked by the characteristic accumulation of abnormal storage material in neurons and other cell types, and a degenerative disease course. All NCLs are characterized by a combination of dementia, epilepsy, and motor decline. For most childhood NCLs, a progressive visual failure is also a core feature. The characteristics of these symptoms can vary and the age at disease onset ranges from birth to young adulthood. Genetic heterogeneity, with fourteen identified NCL genes and wide phenotypic variability render diagnosis difficult. A new NCL classification system based on the affected gene and the age at disease onset allows a precise and practical delineation of an individual patient's NCL type. A diagnostic algorithm to identify each NCL form is presented here. Precise NCL diagnosis is essential not only for genetic counseling, but also for the optimal delivery of care and information sharing with the family and other caregivers. These aspects are challenging because there are also potential long term complications which are specific to NCL type. Therefore care supported by a specifically experienced team of clinicians is recommended. As the underlying pathophysiological mechanism is still unclear for all NCL forms, the development of curative therapies remains difficult. This article is part of a Special Issue entitled: The neuronal ceroid lipofuscinoses or Batten Disease.

Glycosaminoglycans in the blood of hereditary multiple exostoses patients: Half reduction of heparan sulfate to chondroitin sulfate ratio and the possible diagnostic application

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder with wide variation in clinical phenotype and is caused by heterogeneous germline mutations in two of the Ext genes, EXT-1 and EXT-2, which encode ubiquitously expressed glycosyltransferases involved in the polymerization of heparan sulfate (HS) chains. To examine whether the Ext mutation could affect HS structures and amounts in HME patients being heterozygous for the Ext genes, we collected blood from patients and healthy individuals, separated it into plasma and cellular fractions and then isolated glycosaminoglycans (GAGs) from those fractions. A newly established method consisting of a combination of selective ethanol precipitation of GAGs, digestion of GAGs recovered on the filter-cup by direct addition of heparitinase or chondroitinase reaction solution and subsequent high-performance liquid chromatography of the unsaturated disaccharide products enabled the analysis using the least amount of blood (200 µL). We found that HS structures of HME patients were almost similar to those of controls in both plasma and cellular fractions. However, interestingly, although both the amounts of HS and chondroitin sulfate (CS) varied depending on the different individuals, the amounts of HS in both the plasma and cellular fractions of HME patient samples were decreased and the ratios of HS to CS (HS/CS) of HME patient samples were almost half those of healthy individuals. The results suggest that HME patients' blood exhibited reduced HS amounts and HS/CS ratios, which could be used as a diagnostic biomarker for HME.

TS or not TS?

A 47-year-old woman had first presented in her late twenties with complex partial seizures and became seizure-free on carbamazepine. She re-presented 13 years later with migrainous headaches. MR scan of...

Pituitary Stalk Interruption Syndrome and Isolated Pituitary Hypoplasia May Be Caused by Mutations in Holoprosencephaly-Related Genes

Holoprosencephaly (HPE) is a developmental defect characterized by wide phenotypic variability, ranging from minor midline malformations (eg, single central incisor) to severe deformities. In 10-15% of HPE patients, mutations in specific genes have been identified (eg, SHH, TGIF, SIX3). Pituitary stalk interruption syndrome (PSIS) constitutes a distinct abnormality of unknown pathogenesis, whereas isolated pituitary hypoplasia (IPH) has been linked to various developmental genes. Three of our patients with PSIS had a single central incisor, a malformation encountered in some HPE cases. Based on this observation, we initiated a search for mutations in HPE-associated genes in 30 patients with PSIS or IPH. The entire coding region of the TGIF, SHH, and SIX3 genes was sequenced in patients with combined pituitary hormone deficiency associated with either PSIS or IPH and in healthy controls. Two novel mutations in the HPE-related genes were detected (ie, c.799 C>T, p.Q267X in the TGIF gene, and c.1279G>A, p.G427R in the SHH gene) in 2 of our patients. The overall incidence of HPE-related gene mutations in our nonsyndromic and nonchromosomal patients was 6.6%. No molecular defect in the SIX3 gene was detected in our cohort. The data suggest that HPE-related gene mutations are implicated in the etiology of isolated pituitary defects (PSIS or IPH). Alternatively, PSIS or IPH may constitute mild forms of an expanded HPE spectrum.

Síndrome de Hanhart: caso clínico

Introduction: In 1950, Hanhart described three cases of aglossia and limb malformations. The association of congenital oromandibular and limb malformations is rare and has a wide phenotypic variability among the cases described. Case Report: Pregnancy with prenatal ultrasound diagnosis (24 weeks) of agenesis of the right foot, absence of the first finger of the left foot and presence of only the first phalange of the first and fifth fingers of the left hand. At 38 weeks of gestation, a male newborn was born with generalized hypotonia and respiratory distress requiring resuscitation. Physical examination showed microretrognathia, microstomy and several bone malformations of the hands and feet. From the first hours of life he presented progressive apneas with dessaturation, dying as result of one of those episodes. Discussion: The association of microstomy, microretrognathia, hypoglossia, limb malformations and signs suggestive of cranial nerve compromise, allows us to establish the clinical diagnosis of Hanhart Syndrome. The diagnosis is not always easy, given the wide phenotypic variability.

Classification of Genetic Variation for Drought Tolerance in Tall Fescue using Physiological Traits and Molecular Markers

ABSTRACTDrought stress is a major factor limiting turfgrass growth. The objectives of the study were to determine genetic variation in major physiological traits associated with drought tolerance in a collection of tall fescue (Festuca arundinacea Schreb.) germplasm and to examine genetic diversity and relationships among germplasm varying in drought tolerance via molecular marker classification. Plants of 44 accessions from Africa, Europe, America, and Australia were exposed to well‐watered conditions or drought stress by withholding irrigation for 11 d in a trial conducted in June 2009 and for 13 d during a repeated trial conducted in September 2009 in a greenhouse. Visual evaluation of turf quality, leaf relative water content, electrolyte leakage, chlorophyll content, and evapotranspiration rate demonstrated wide phenotypic variation contributing to drought tolerance in this collection of tall fescue germplasm. A hierarchical cluster analysis was conducted based on physiological traits and among 44 tall fescue accessions, 12 accessions were classified as most tolerant, 17 as moderately tolerant, and 15 as susceptible. The genetic similarity matrix from molecular marker analysis demonstrated similarity indexes ranging from 0.51 to 0.83. Among the 44 accessions, SH‐3‐AM‐US from America and PI598949‐EU‐IT from Europe were genetically distinct, but both were classified as drought‐tolerant germplasm based on physiological data. Screening genetically diverse germplasm to identify superior drought tolerance through the combined approach of physiological and molecular marker analysis could prove useful in breeding programs for further improvement of drought tolerance in tall fescue turfgrass.

Molecular Basis, Diagnosis and Clinical Management of Mucopolysaccharidoses

Mucopolysaccharidoses (MPSs) are a group of hereditary, monogenic disorders caused by lysosomal storage of glycosaminoglycans. Their incidence as a group is between 1:25,000 and 1:45,000. At present 11 different enzyme deficiencies are know to be responsible of 7 similar but distinct diseases. The diagnosis is suspected clinically but must be confirmed through biochemical, enzymatic and molecular analysis. Prenatal diagnosis is feasible for each disease. The phenotype worsens with age, due to progressive storage, and mainly involves mucosal tissue, upper airways and lungs, bones and joints, central and peripheral nervous system, heart, liver, eye and ear. Any type of MPSs, is characterized by a wide variability of phenotype ranging from a severe fetal-neonatal disease to an attenuated form diagnosed in adult individuals. Recently new treatments, like hematopoietic stem cell transplantation and enzymatic replacement therapy, became available for many of these disorders entailing the urgency of early diagnosis to allow access to therapies. Thanks to therapies these patients have a longer life than in the past and this implies that also palliative treatments, of which the cardiological ones have a prominent part, must be undertaken diligently. The cardiologist may face, more frequently than expected, with the need to diagnose a patient with MPS who was not recognized by other specialists. The echocardiographic features of these patients are typical and may help in the clinical diagnosis. The future probably deserves to these disorders other new treatments or combination therapies, which might further improve prognosis of these diseases.

Whole Genome Association Mapping of Fusarium Head Blight Resistance in European Winter Wheat (Triticum aestivum L.)

A total of 358 recent European winter wheat varieties plus 14 spring wheat varieties were evaluated for resistance to Fusarium head blight (FHB) caused by Fusarium graminearum and Fusarium culmorum in four separate environments. The FHB scores based on FHB incidence (Type I resistance)×FHB severity (Type II resistance) indicated a wide phenotypic variation of the varieties with BLUE (best linear unbiased estimation) values ranging from 0.07 to 33.67. Genotyping with 732 microsatellite markers resulted in 782 loci of which 620 were placed on the ITMI map. The resulting average marker distance of 6.8 cM allowed genome wide association mapping employing a mixed model. Though no clear population structure was discovered, a kinship matrix was used for stratification. A total of 794 significant (−log10(p)-value≥3.0) associations between SSR-loci and environment-specific FHB scores or BLUE values were detected, which included 323 SSR alleles. For FHB incidence and FHB severity a total of 861 and 877 individual marker-trait associations (MTA) were detected, respectively. Associations for both traits co-located with FHB score in most cases. Consistent associations detected in three or more environments were found on all chromosomes except chromosome 6B, and with the highest number of MTA on chromosome 5B. The dependence of the number of favourable and unfavourable alleles within a variety to the respective FHB scores indicated an additive effect of favourable and unfavourable alleles, i.e. genotypes with more favourable or less unfavourable alleles tended to show greater resistance to FHB. Assessment of a marker specific for the dwarfing gene Rht-D1 resulted in strong effects. The results provide a prerequisite for designing genome wide breeding strategies for FHB resistance.

Rhodopsin p.N78I dominant mutation causing sectorial retinitis pigmentosa in a pedigree with intrafamilial clinical heterogeneity

ObjectiveThe purpose of this study was to determine the molecular basis of retinitis pigmentosa (RP) in a 4 affected sib-family segregating this retinal phenotype. MethodsAffected sibs underwent complete ophthalmologic examination including funduscopic inspection, electroretinogram, fluorescein angiography, visual field measurement, and optical coherence tomography. Both parents were deceased after their sixties and were reported with no visual handicap. Molecular analysis included direct nucleotide sequencing of the rhodopsin gene (RHO), at chromosome 3q21–q24, in DNA from a total of 4 affected sibs. A total of 200 ethnically matched alleles were included as mutation controls. ResultsSector RP was clinically documented in this family. Wide phenotypic variability was observed with visual acuities ranging from 20/20 to 20/200 and variable funduscopic appearance. Molecular analysis disclosed a c.233A>T mutation at RHO exon 1, predicting a missense p.N78I substitution. ConclusionsEven though RP can be caused by mutations in a variety of genes, the RHO gene was chosen to be investigated in this RP family since it has been previously associated to sector disease. This case exemplifies the value of guiding RP molecular analysis based on funduscopic features.

Fluctuating selection and immigration as determinants of the phenotypic composition of a population

It is important to identify the factors that affect the evolutionary potential of populations to respond to environmental changes. Such processes are for example the ones affecting the amount of heritable phenotypic variation in a population. We examined factors explaining the wide phenotypic variation in the genetically determined black-brown dorsal colouration of male pied flycatchers (Ficedula hypoleuca) during a period of >50 years in a northern European breeding population. We demonstrate that the temperature-dependent relative breeding success of brown males predicts the inter-annual change in the proportion of the brown male phenotype. The proportion of brown males also appears to reflect immigration from Central Europe, where the brown type prevails due to local selection pressure. Warm springs in northern Central Europe had a positive effect on the proportion of the brown phenotype in the north in the early part of the study period, which suggests prolonged migration in favourable conditions. However, the association between warm springs and a high proportion of brown males has weakened from the 1950s to the present, which may explain why the proportion of the brown males in our study area decreased by a third during the period 1954 to 2008. This is likely a result of decreasing population size in Central Europe. These results demonstrate that temporal variation in environmental conditions is maintaining variation in the pied flycatcher male phenotype. They also indicate that climate warming has the potential to change the population composition both through temperature-dependent selection and environmental factors affecting long-distance immigration.

Genotype–phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Over the last two decades, we have extensively studied the genetics of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH) and have performed 8,290 DNA analyses of the CYP21A2 gene on members of 4,857 families at risk for CAH--the largest cohort of CAH patients reported to date. Of the families studied, 1,507 had at least one member affected with one of three known forms of CAH, namely salt wasting, simple virilizing, or nonclassical CAH. Here, we report the genotype and phenotype of each affected patient, as well as the ethnic group and country of origin for each patient. We showed that 21 of 45 genotypes yielded a phenotypic correlation in our patient cohort. In particular, contrary to what is generally reported in the literature, we found that certain mutations, for example, the P30L, I2G, and I172N mutations, yielded different CAH phenotypes. In salt wasting and nonclassical CAH, a phenotype can be attributed to a genotype; however, in simple virilizing CAH, we observe wide phenotypic variability, particularly with the exon 4 I172N mutation. Finally, there was a high frequency of homozygous I2G and V281L mutations in Middle Eastern and Ashkenazi Jewish populations, respectively. By identifying the predominant phenotype for a given genotype, these findings should assist physicians in prenatal diagnosis and genetic counseling of parents who are at risk for having a child with CAH.

Mapping the Complex Morphology of Cell Interactions with Nanowire Substrates Using FIB-SEM

Using high resolution focused ion beam scanning electron microscopy (FIB-SEM) we study the details of cell-nanostructure interactions using serial block face imaging. 3T3 Fibroblast cellular monolayers are cultured on flat glass as a control surface and on two types of nanostructured scaffold substrates made from silicon black (Nanograss) with low- and high nanowire density. After culturing for 72 hours the cells were fixed, heavy metal stained, embedded in resin, and processed with FIB-SEM block face imaging without removing the substrate. The sample preparation procedure, image acquisition and image post-processing were specifically optimised for cellular monolayers cultured on nanostructured substrates. Cells display a wide range of interactions with the nanostructures depending on the surface morphology, but also greatly varying from one cell to another on the same substrate, illustrating a wide phenotypic variability. Depending on the substrate and cell, we observe that cells could for instance: break the nanowires and engulf them, flatten the nanowires or simply reside on top of them. Given the complexity of interactions, we have categorised our observations and created an overview map. The results demonstrate that detailed nanoscale resolution images are required to begin understanding the wide variety of individual cells’ interactions with a structured substrate. The map will provide a framework for light microscopy studies of such interactions indicating what modes of interactions must be considered.

Heterogeneity in the entire genome for three genotypes of peach [Prunus persica (L.) Batsch] as distinguished from sequence analysis of genomic variants

BackgroundPeach [Prunus persica (L.) Batsch] is an economically important fruit crop that has become a genetic-genomic model for all Prunus species in the family Rosaceae. A doubled haploid reference genome sequence length of 227.3 Mb, a narrow genetic base contrasted by a wide phenotypic variability, the generation of cultivars through hybridization with subsequent clonal propagation, and the current accessibility of many founder genotypes, as well as the pedigree of modern commercial cultivars make peach a model for the study of inter-cultivar genomic heterogeneity and its shaping by artificial selection.ResultsThe quantitative genomic differences among the three genotypes studied as genomic variants, included small variants (SNPs and InDels) and structural variants (SV) (duplications, inversions and translocations). The heirloom cultivar 'Georgia Belle’ and an almond by peach introgression breeding line 'F8,1-42’ are more heterogeneous than is the modern cultivar 'Dr. Davis’ when compared to the peach reference genome ('Lovell’). A pair-wise comparison of consensus genome sequences with 'Lovell’ showed that 'F8,1-42’ and 'Georgia Belle’ were more divergent than were 'Dr. Davis’ and 'Lovell’.ConclusionsA novel application of emerging bioinformatics tools to the analysis of ongoing genome sequencing project outputs has led to the identification of a range of genomic variants. Results can be used to delineate the genomic and phenotypic differences among peach genotypes. For crops such as fruit trees, the availability of old cultivars, breeding selections and their pedigrees, make them suitable models for the study of genome shaping by artificial selection. The findings from the study of such genomic variants can then elucidate the control of pomological traits and the characterization of metabolic pathways, thus facilitating the development of protocols for the improvement of Prunus crops.Electronic supplementary materialThe online version of this article (doi: 10.1186/1471-2164-14-750) contains supplementary material, which is available to authorized users.

Spinocerebellar ataxia type 7: Report of an Indian family

Spinocerebellar ataxia type 7 (SCA7) is a form of autosomal dominant cerebellar ataxia which is associated with pigmentary retinal degeneration. It is known for its world-wide rarity except in the Scandinavian countries. It is very rarely reported from India and the neighbouring Asian countries. The present report describes the neurogenetic findings of a family of SCA7, from the northern part of Karnataka in South India. It documents the wide intrafamilial phenotypic variability, which could be correlated with the CAG repeat counts and phenomenon of anticipation. Genotype phenotype correlation highlighted certain disparities in comparison with the previous studies. The report highlights the need for multiethnic population studies and the role of genetic counseling and prenatal testing in SCA7 patients.

A rare chronic progressive leukoencephalopathy of childhood: Two newborn cases with vanishing white matter disease

Vanishing white matter disease, which is one of the most prevalent inherited childhood leukoencephalopathies, has an extremely wide phenotypic variation. The classical phenotype is characterized by early childhood onset of chronic neurological deterioration, dominated by cerebellar ataxia. However cases with antenatal onset, severe clinical course in the neonatal period and early demise have been also defined in the literature. Almost all diagnosed newborns present with rapid neurological deterioration and unexplained coma soon after birth. Other symptoms include feeding intolerance, hypotonia, seizures, apnea and severe respiratory distress. The exact pathogenesis is not known. Cerebral magnetic resonance imaging and spectroscopy are diagnostic. Differential diagnosis is difficult in the neonatal period and the disease may be misdiagnosed as hypoxic ischemic encephalopathy, congenital infections and inborn errors of metabolism. Here we present two premature infants with unexplained comatose state and severe neurological symptoms whose cerebral imaging studies were indicative of rarefaction and cystic degeneration of the cerebral white matter, and particularly emphasize on the differential diagnosis and the importance of cerebral imaging studies in the newborn period.