Correction: Corrigendum: The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype–phenotype correlations

Genet Med 18: 1143–1150; doi:10.1038/gim.2016.18 In the originally published article, the x axis of figure 1b was incorrectly labeled. The correct figure appears below:     

Phenotypic spectrum and genotype–phenotype correlations of NRXN1 exon deletions

Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the β isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.     

Genetics,genomics, and genotype–phenotype correlations of TSC: Insights for clinical practice

Tuberous Sclerosis Complex (TSC) is a multisystem autosomal dominant condition caused by inactivating pathogenic variants in either the TSC1 or the TSC2 gene, leading to hyperactivation of the mTOR pathway. Here, we present an update on the genetic and genomic aspects of TSC, with a focus on clinical and laboratory practice. We briefly summarize the structure of TSC1 and TSC2 as well as their protein products, and discuss current diagnostic testing, addressing mosaicism. We consider genotype–phenotype correlations as an example of precision medicine, and discuss genetic counseling in TSC, with the aim of providing geneticists and health care practitioners involved in the care of TSC individuals with useful tools for their practice.     

Mutation spectrum in the ABCC6 gene and genotype–phenotype correlations in a French cohort with pseudoxanthoma elasticum

PurposePseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by variants in the ABCC6 gene. Ectopic mineralization of connective tissues leads to skin, eye, and cardiovascular manifestations with considerable phenotypic variability of unknown cause. We aimed to identify genotype–phenotype correlations in PXE.MethodsA molecular analysis was performed on 458 French PXE probands clinically evaluated using the Phenodex score (PS). Variant topographic analysis and genotype–phenotype correlation analysis were performed according to the number and type of identified variants.ResultsComplete molecular analysis of 306 cases allowed the identification of 538 mutational events (88% detection rate) with 142 distinct variants, of which 66 were novel. Missense variant distribution was specific to some regions and residues of ABCC6. For the 220 cases with a complete PS, there was a higher prevalence of eye features in Caucasian patients (P = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (P = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11 and 10%, respectively).ConclusionWe propose an updated PS including renal and neurological features and adaptation of follow-up according to the genetic and ethnic status of PXE-affected patients.Genet Med advance online publication 19 January 2017     

Delineation of C12orf65-related phenotypes: a genotype–phenotype relationship

C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. In four family members affected with childhood-onset optic atrophy accompanied by slowly progressive peripheral neuropathy and spastic paraparesis, we identified a homozygous frame shift mutation c.413_417 delAACAA, which predicts a truncated protein lacking the C-terminal portion. In the second family, we studied three affected individuals who presented with early onset optic atrophy, peripheral neuropathy, and spastic gait in addition to moderate intellectual disability. Muscle biopsy in two of the patients revealed decreased activities of the mitochondrial respiratory chain complexes I and IV. In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. In addition, a clear genotype–phenotype correlation is anticipated in which deleterious mutations which disrupt the GGQ-containing domain in the first coding exon are expected to result in a more severe phenotype, whereas down-stream C-terminal mutations may result in a more favorable phenotype, typically lacking cognitive impairment.     

Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients

PurposePathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis.MethodsIndividuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods.ResultsOne hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH).ConclusionWe define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.     

Expanding the clinical and mutational spectrum of the Ehlers–Danlos syndrome,dermatosparaxis type

PurposeThe Ehlers–Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility.MethodsWe report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition.ResultsWe identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients.ConclusionThis study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS.Genet Med 18 9, 882–891.     

The Wiskott–Aldrich syndrome: from genotype–phenotype correlation to treatment

Development of patient-tailored prognostic and therapeutic strategies remains a major, yet largely unmet, goal of medicine. Studies performed in patients who carry mutations in the Wiskott–Aldrich syndrome protein (WASP) gene have indicated the feasibility, but also the limitations, of this approach. In this review, we discuss the importance of specific WASP mutations, and their effects on protein expression and function in determining the spectrum of clinical phenotypes associated with WASP defects. The array of currently available and foreseeable therapeutic options is reviewed in this context as a model for other more common genetic disorders.     

Genetic epidemiology,prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype–phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the α1-chain were associated with blue sclera (P=0.0110). Comparing glycine with serine substitutions, α1-alterations were associated with more severe phenotype (P=0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P<0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population.     

The spectrum of neurological manifestations and genotype–phenotype correlation in Indian children with Gaucher disease

Gaucher disease (GD), one of the most frequent autosomal recessive lysosomal storage disorders, occurs due to bi-allelic pathogenic variants in the GBA1. Worldwide, the c.1448T>C (L483P) homozygous pathogenic variant is reported to be associated with neurological GD phenotype. Clinical distinction between GD1 and GD3 may be challenging due to subtle neurological features. Objective methods to evaluate neurological signs and saccades may help in early diagnosis. This study was conducted to assess the neurological phenotype, and its severity using a modified severity scoring tool (mSST), and the genotype–phenotype correlation. A total of 45 children aged 2 years 6 months to 15 years with a confirmed enzymatic and molecular diagnosis of GD with or without therapy were recruited. mSST tool was used to assess the severity of the neurological phenotype. A digital eye movement tracker (View Point Tracker) was used to assess eye movements. Clinical and genetic findings were analyzed. Out of 45 patients, 39 (86.7%) had at least one neurological phenotype detected using the mSST tool, with impairment of cognitive function (68.8%, 31/45) being the commonest feature. Thirty-two of 45 (71%) were assessed for saccadic eye movements using the eye tracker. Of these, 62.5% (20/32) had absent saccades. Four children (8.9%, 4/32) without clinical oculomotor apraxia had absent saccades on the viewpoint eye tracker. Overall, 77.7% (35/45), had homozygosity for c.1448T>C in GBA1 of which 91.4% (32/35) had neurological manifestations. Other alleles associated with neurological phenotype included c.1603C>T(p.R535C), c.1184C>T (p.S395F), c.115+1G>A (g.4234G>A), c.260G>A (p.R87Q) and c.1352A>G (p.Y451C). To conclude, in India, the c.1448T>C pathogenic variant in GBA1 is the commonest  and is associated with neurological phenotype of GD. Therefore, every patient of GD should be assessed using the mSST scoring tool for an early pick up of neurological features. The routine use of a viewpoint eye tracker in children with GD would be useful for early recognition of saccadic abnormalities.     

A mixed-methods investigation of sensory response patterns in Barth syndrome: a clinical phenotype?

Barth syndrome is a genetic disorder that affects approximately 1/500,000 boys each year. While treatment of medical complications associated with Barth is of primary importance, there is a concomitant need to look at behavioral and clinical features of the disorder. The purpose of this study was to examine the prevalence of atypical sensory processing in 21 boys with Barth syndrome and to explore if phenotypic patterns of sensory responsiveness may be useful in early diagnosis. Using a mixed methods approach, we found that sensory issues related to feeding and eating were ubiquitous in our sample, with some behaviors such as strong gag reflex identifiable early in development. Specifically, boys with Barth had a strong preference for salty, cheesy, and spicy foods while having an overall restricted repertoire of foods they would eat (e.g., picky eaters). In boys with Barth as they age, auditory sensitivity and auditory filtering issues also emerged as potential sensory-related behaviors affecting academic performance and participation. Overall, this study suggests that early identification of sensory patterns in Barth may assist in differential diagnosis and create opportunities for early interventions that may minimize the impact of these behaviors on function and participation.     

Growth charts for Marfan syndrome in the Netherlands and analysis of genotype–phenotype relationships

To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS-related height increase across populations. Height and weight data of individuals with MFS aged 0–21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype–phenotype relationships, FBN1 variant type was included as an independent variable in height-for-age and BMI-for-age models. MFS-related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height-for-age, BMI-for-age, and weight-for-height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1-HI variants were associated with taller height in both sexes, and decreased BMI in females (p-values <0.05). This Dutch MFS growth study broadens the notion that genetic background and MFS variant type (HI/DN) influence tall and slender stature in MFS.     

Evaluating the quality of Marfan genotype–phenotype correlations in existing FBN1 databases

BackgroundGenetic FBN1 testing is pivotal for confirming the clinical diagnosis of Marfan syndrome. In an effort to evaluate variant causality, FBN1 databases are often used. We evaluated the current databases regarding FBN1 variants and validated associated phenotype records with a new Marfan syndrome geno-phenotyping tool called the Marfan score.Methods and resultsWe evaluated four databases (UMD-FBN1, ClinVar, the Human Gene Mutation Database (HGMD), and Uniprot) containing 2,250 FBN1 variants supported by 4,904 records presented in 307 references. The Marfan score calculated for phenotype data from the records quantified variant associations with Marfan syndrome phenotype. We calculated a Marfan score for 1,283 variants, of which we confirmed the database diagnosis of Marfan syndrome in 77.1%. This represented only 35.8% of the total registered variants; 18.5–33.3% (UMD-FBN1 versus HGMD) of variants associated with Marfan syndrome in the databases could not be confirmed by the recorded phenotype.ConclusionFBN1 databases can be imprecise and incomplete. Data should be used with caution when evaluating FBN1 variants. At present, the UMD-FBN1 database seems to be the biggest and best curated; therefore, it is the most comprehensive database. However, the need for better genotype–phenotype curated databases is evident, and we hereby present such a database.Genet Med advance online publication 01 December 2016     

Geleophysic and acromicric dysplasias: natural history,genotype–phenotype correlations,and management guidelines from 38 cases

PurposeGeleophysic dysplasia (GD) and acromicric dysplasia (AD) are characterized by short stature, short extremities, and progressive joint limitation. In GD, cardiorespiratory involvement can result in poor prognosis. Dominant variants in the FBN1 and LTBP3 genes are responsible for AD or GD, whereas recessive variants in the ADAMTSL2 gene are responsible for GD only. The aim of this study was to define the natural history of these disorders and to establish genotype–phenotype correlations.MethodsThis monocentric retrospective study was conducted between January 2008 and December 2018 in a pediatric tertiary care center and included patients with AD or GD with identified variants (FBN1, LTBP3, or ADAMTSL2).ResultsTwenty-two patients with GD (12 ADAMTSL2, 8 FBN1, 2 LTBP3) and 16 patients with AD (15 FBN1, 1 LTBP3) were included. Early death occurred in eight GD and one AD. Among GD patients, 68% presented with heart valve disease and 25% developed upper airway obstruction. No AD patient developed life-threatening cardiorespiratory issues. A greater proportion of patients with either a FBN1 cysteine variant or ADAMTSL2 variants had a poor outcome.ConclusionGD and AD are progressive multisystemic disorders with life-threatening complications associated with specific genotype. A careful multidisciplinary follow-up is needed.     

Insights into the genotype–phenotype relationship of ocular manifestations in Kabuki syndrome

We aim to assess if genotype–phenotype correlations are present within ocular manifestations of Kabuki syndrome (KS) among a large multicenter cohort. We conducted a retrospective, medical record review including clinical history and comprehensive ophthalmological examinations of a total of 47 individuals with molecularly confirmed KS and ocular manifestations at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center. We assessed information regarding ocular structural, functional, and adnexal elements as well as pertinent associated phenotypic features associated with KS. For both type 1 KS (KS1) and type 2 KS (KS2), we observed more severe eye pathology in nonsense variants towards the C-terminus of each gene, KMT2D and KDM6A, respectively. Furthermore, frameshift variants appeared to be not associated with structural ocular elements. Between both types of KS, ocular structural elements were more frequently identified in KS1 compared with KS2, which only involved the optic disc in our cohort. These results reinforce the need for a comprehensive ophthalmologic exam upon diagnosis of KS and regular follow-up exams. The specific genotype may allow risk stratification of the severity of the ophthalmologic manifestation. However, additional studies involving larger cohorts are needed to replicate our observations and conduct powered analyses to more formally risk-stratify based on genotype, highlighting the importance of multicenter collaborations in rare disease research.     

The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders?

BACKGROUND: The present analyses were designed to compare the clinical characteristics and long-term episode course of Bipolar-I and Bipolar-II patients in order to help clarify the relationship between these disorders and to test the bipolar spectrum hypothesis. METHODS: The patient sample consisted of 135 definite RDC Bipolar-I (BP-I) and 71 definite RDC Bipolar-II patients who entered the NIMH Collaborative Depression Study (CDS) between 1978 and 1981; and were followed systematically for up to 20 years. Groups were compared on demographic and clinical characteristics at intake, and lifetime comorbidity of anxiety and substance use disorders. Subsets of patients were compared on the number and type of affective episodes and the duration of inter-episode well intervals observed during a 10-year period following their resolution of the intake affective episode. RESULTS: BP-I and BP-II had similar demographic characteristics and ages of onset of their first affective episode. Both disorders had more lifetime comorbid substance abuse disorders than the general population. BP-II had a significantly higher lifetime prevalence of anxiety disorders in general, and social and simple phobias in particular, compared to BP-I. Intake episodes of BP-I were significantly more acutely severe. BP-II patietns had a substantially more chronic course, with significantly more major and minor depressive episodes and shorter inter-episode well intervals. BP-II patients were prescribed somatic treatment a substantially lower percentage of time during and between affective episodes. LIMITATIONS: BP-I patients with severe manic course are less likely to be retained in long-term follow-up, whereas the reverse might be true for BP-II patients who are significantly more prone to depression (i.e., patients with less inclination to depression and with good prognosis may have dropped out in greater proportions); this could increase the gap in long term course characteristics between the two samples. The greater chronicity of BP-II may be due, in part, to the fact that the patients were prescribed somatic treatments substantially less often both during and between affective episodes. CONCLUSIONS: The variety in severity of the affective episodes shows that bipolar disorders, similar to unipolar disorders, are expressed longitudinally during their course as a dimensional illness. The similarities of the clinical phenotypes of BP-I and BP-II, suggest that BP-I and BP-II are likely to exist in a disease spectrum. They are, however, sufficiently distinct in terms of long-term course (i.e., BP-I with more severe episodes, and BP-II more chronic with a predominantly depressive course), that they are best classified as two separate subtypes in the official classification systems.