Objective
Studies have shown that prenatal exome sequencing (PES) improves diagnostic yield in cases of fetal structural malformation. We have retrospectively analysed PES cases from two of the ...largest fetal medicine centres in the UK to determine the impact of results on management of a pregnancy.
Design
A retrospective review of clinical case notes.
Setting
Two tertiary fetal medicine centres.
Population
Pregnancies with fetal structural abnormalities referred to clinical genetics via a multidisciplinary team.
Methods
We retrospectively reviewed the notes of all patients who had undergone PES. DNA samples were obtained via chorionic villus sampling or amniocentesis. Variants were filtered using patient‐specific panels and interpreted using American College of Medical Genetics guidelines.
Results
A molecular diagnosis was made in 42% (18/43) ongoing pregnancies; of this group, there was a significant management implication in 44% (8/18). A positive result contributed to the decision to terminate a pregnancy in 16% (7/43) of cases. A negative result had a significant impact on management in two cases by affirming the decision to continue pregnancy.
Conclusions
We demonstrate that the results of PES can inform pregnancy management. Challenges include variant interpretation with limited phenotype information. These results emphasise the importance of the MDT and collecting phenotype and variant data. As this testing is soon to be widely available, we should look to move beyond diagnostic yield as a measure of the value of PES.
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Prenatal exome sequencing can aid decision‐making in pregnancy management; review ahead of routine implementation in NHS.
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Prenatal exome sequencing can aid decision making in pregnancy management; review ahead of routine implementation in NHS.
Abstract
Background
The severity of Tuberous Sclerosis Complex (TSC) can vary among affected individuals. Complications of TSC can be life threatening, with significant impact on patients’ quality of ...life. Management may vary dependent on treating physician, local and national policies, and funding. There are no current UK guidelines. We conducted a Delphi consensus process to reach agreed guidance for the management of patients with TSC in the UK.
Methods
We performed a literature search and reviewed the 2012/13 international guideline for TSC management. Based on these, a Delphi questionnaire was formed. We invited 86 clinicians and medical researchers to complete an online survey in two rounds. All the people surveyed were based in the UK. Clinicians were identified through the regional TSC clinics, and researchers were identified through publications. In round one, 55 questions were asked. In round two, 18 questions were asked in order to obtain consensus on the outstanding points that had been contentious in round one. The data was analysed by a core committee and subcommittees, which consisted of UK experts in different aspects of TSC. The Tuberous Sclerosis Association was consulted.
Results
About 51 TSC experts took part in this survey. Two rounds were required to achieve consensus. The responders were neurologists, nephrologists, psychiatrist, psychologists, oncologists, general paediatricians, dermatologist, urologists, radiologists, clinical geneticists, neurosurgeons, respiratory and neurodisability clinicians.
Conclusions
These new UK guidelines for the management and surveillance of TSC patients provide consensus guidance for delivery of best clinical care to individuals with TSC in the UK.
To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy ...involving SCN9A.
An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals.
Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete.
Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.
Aim
To investigate the interdependence between risk factors associated with long‐term intellectual development in individuals with tuberous sclerosis complex (TSC).
Method
The Tuberous Sclerosis 2000 ...Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2.
Results
Intellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence.
Interpretation
Early‐onset and severe epilepsy in the first 2 years of life are associated with increased risk of long‐term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy.
What this paper adds
Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC).
Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings.
Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability.
Risk pathways through seizures in the first 2 years predict long‐term cognitive outcomes in individuals with TSC.
What this paper adds
Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC).
Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings.
Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability.
Risk pathways through seizures in the first 2 years predict long‐term cognitive outcomes in individuals with TSC.
This article is commented on by Curatolo on page 269 of this issue.
The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected ...worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5–1.0 per 1000 and a ratio of sibling risk to population prevalence (λs) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the a4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the α7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at α = 0.65; Zall = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.
Summary
Primary erythermalgia (erythromelalgia) is a rare autosomal dominant condition characterized by intermittent attacks of erythema, increased skin temperature and severe burning pain in the ...extremities, in a bilateral symmetrical distribution. Mutations in the SCN9A gene, which encodes a voltage‐gated sodium channel have been shown to cause this disease. We report a family identified to have a mutation in the SCN9A gene, in which one severely affected family member has responded to the therapeutic combination of gabapentin and carbamazepine treatment.
Whole‐exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, ...developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2‐related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients.
This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2‐related disorder and the Angelman‐/Rett‐/Pitt‐Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2‐related disorder.
Features found in patients with IQSEC2 variants.
Study Type – Therapy (case series) Level of Evidence 4
OBJECTIVE
To examine the presentation, management and outcomes of patients with renal angiomyolipoma (AML) over a period of 10 years, at St ...George’s Hospital, London, UK.
PATIENTS AND METHODS
We assessed retrospectively 102 patients (median follow‐up 4 years) at our centre; 70 had tuberous sclerosis complex (TSC; median tumour size 3.5 cm) and the other 32 were sporadic (median tumour size 1.2 cm). Data were gathered from several sources, including radiology and clinical genetics databases. The 77 patients with stable disease were followed up with surveillance imaging, and 25 received interventions, some more than one. Indications for intervention included spontaneous life‐threatening haemorrhage, large AML (10–20 cm), pain and visceral compressive symptoms.
RESULTS
Selective arterial embolization (SAE) was performed in 19 patients; 10 received operative management and four had a radiofrequency ablation (RFA). SAE was effective in controlling haemorrhage from AMLs in the acute setting (six) but some patients required further intervention (four) and there was a significant complication rate. The reduction in tumour volume was only modest (28%). No complications occurred after surgery (median follow‐up 5.5 years) or RFA (median follow‐up 9 months). One patient was entered into a trial and treated with sirolimus (rapamycin).
CONCLUSIONS
The management of AML is both complex and challenging, especially in those with TSC, where tumours are usually larger and multiple. Although SAE was effective at controlling haemorrhage in the acute setting it was deemed to be of limited value in the longer term management of these tumours. Thus novel techniques such as focused ablation and pharmacological therapies including the use of anti‐angiogenic molecules and mTOR inhibitors, which might prove to be safer and equally effective, should be further explored.
Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain ...with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene
SCN9A, which encodes hNa
v1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na
v1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in
SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy.
Hyperekplexia is a rare condition characterised by the presence of neonatal hypertonia and an exaggerated startle response. Mutations have been described in GLRA1, the gene encoding the alpha 1 ...subunit of the glycine receptor, in dominant families with hyperekplexia and in a single sporadic case, thought to represent an autosomal recessive form of the disease. In this study the coding region of the GLRA1 was analysed in eight probands with hyperekplexia by restriction digest and sequencing. Two familial cases were found to possess the previously described G1192A (R271Q) mutation in exon 6. In an additional family in which hyperekplexia cosegregates with spastic paraparesis, a novel A to G transversion at nucleotide 1206 in exon 6 was detected that changes a lysine at amino acid 276 to a glutamate (K276E). In four sporadic cases no mutations were found. In addition, one familial case did not have a mutation in the coding region of the gene.
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