Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

Background

An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine‐to‐histidine substitution at codon 337 of TP53 (R337H), has not been determined.

Objective

To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation.

Methods

The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non‐carrier and 695 (including the 40 probands) from the carrier parental lines.

Results

40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li‐Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li‐Fraumeni‐like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%).

Conclusions

The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.     

Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing

Background

Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention in the family. Probands are traditionally left to inform their relatives about the increased risk, but distant relatives may remain uninformed. An approach to contacting directly at‐risk persons assumed to be unaware of their increased cancer risk was taken. With cancer prevention as the ultimate goal, the study was aimed at investigating attitudes towards and psychosocial consequences of this novel strategy.

Methods

In families with hereditary non‐polyposis colorectal cancer (Lynch syndrome), 286 healthy adult relatives with a 50% risk of a predisposing mutation were contacted by letter. Of these, 112 participated in counselling and predictive testing. Baseline information and information obtained 1 month after the test for 73 respondents were compared with 299 corresponding subjects, approached via the proband (family‐mediated approach in our previous study) in these families.

Results

After the contact letter, 51% consented to the study. Of these, 92% approved of the direct contact and 33% had tried to seek information. In 34% of the mutation carriers, neoplasia was identified in the first post‐test colonoscopy. Although post‐test fear of cancer increased among the mutation carriers and decreased among noncarriers, almost all participants were satisfied with their decision to participate, independently of their test results, parallel to the family‐mediated approach.

Conclusion

In this large‐scale study, relatives in cancer families were actively contacted to inform them of the condition and genetic counselling. Their attitudes were encouraging, and the psychosocial consequences were similar to the family‐mediated approach. Our results suggest the appropriateness of direct contact as an alternative method of contact in cases of life‐threatening treatable disease.     

Genetic and epigenetic defects at the 6q24 imprinted locus in a cohort of 13 patients with transient neonatal diabetes: new hypothesis raised by the finding of a unique case with hemizygotic deletion in the critical region

Background

Transient neonatal diabetes (TND) is a rare form of diabetes usually present in the first few days after birth that resolves within 1 year but that has a tendency to recur later in life. It can be associated with chromosome 6 paternal uniparental disomy (UPD), paternal duplications or loss of maternal methylation at the 6q24 imprinted locus.

Objective

To report on a cohort of 13 sporadic TND cases, including five with birth defects (congenital abnormalities of heart, brain and bone) and eight without.

Results

The hallmarks of diabetes were similar in patients with or without 6q24 defects. The chromosome 6 abnormalities in our patients (n = 13) included 2 of 13 (approximately 15.4%) cases of paternal UPD6, 2 of 11 (approximately 18%) cases of complete and 3 of 11 (approximately 27%) cases of partial loss of the maternal methylation signature upstream of ZAC1‐HYMAI imprinted genes in non‐UPD cases, and 1 of 13 (approximately 7.7%) cases of hemizygotic deletion.

Conclusion

The deletion was found in a patient with severe congenital abnormalities. This genetic lesion was not reported previously. The hypothesis of an effect on regulatory elements critical for imprinting and tissue‐specific gene expression in early development by the deletion is raised. The data presented here may contribute to the diagnosis and the understanding of imprinting in the region.     

The T/G 13915 variant upstream of the lactase gene (LCT) is the founder allele of lactase persistence in an urban Saudi population

Background

The prevalence of lactase persistence is high in Saudi Arabia.

Objective

To identify a DNA variant for the lactase persistence/non‐persistence trait in adult Arabs in Saudi Arabia.

Methods

We sequenced DNA from 432 anonymous neonatal blood donors from five different regions of Saudi Arabia to cover the 400 bp region surrounding the previously identified lactase persistence/non‐persistence variant C/T−13910 residing in intron 13 of the MCM6 gene.

Results

Two anonymous blood donors carried the C/T−13910 genotype. One variant, T/G −13915, residing 5 bp upstream of the C/T−13910 variant, was present in 332 of 432 (76.9%) of the neonatal samples, compatible with previous prevalence figures of lactase persistence in urban Saudi populations. Determination of disaccharidase activities in 25 intestinal biopsy samples showed a highly significant correlation between lactase activity and the T/G−13915 genotypes (p<0.001; Fisher exact test) as well as between the L:S ratio and the aforementioned genotypes (p<0.001; Fisher exact test).

Conclusion

The T/G−13915 variant is the founder mutation of lactase persistence in an urban Saudi population. The results obtained here have implications for genetic testing of adult‐type hypolactasia and to analysis of human evolution, the origin of cattle domestication and migrations of the populations in the Arabian peninsula.     

CRYM mutations cause deafness through thyroid hormone binding properties in the fibrocytes of the cochlea

Background

In a search for mutations of μ‐crystallin (CRYM), a taxion specific crystalline which is also known as an NADP regulated thyroid hormone binding protein, two mutations were found at the C‐terminus in patients with non‐syndromic deafness.

Objective

To investigate the mechanism of hearing loss caused by CRYM mutations

Methods

T3 binding activity of mutant μ‐crystallin was compared with that of wild‐type μ‐crystallin, because μ‐crystallin is known to be identical to T3 binding protein. To explore the sites within the cochlea where μ‐crystallin is functioning, its localisation in the mouse cochlea was investigated immunocytochemically using a specific antibody.

Results

One mutant was shown to have no binding capacity for T3, indicating that CRYM mutations cause auditory dysfunction through thyroid hormone binding properties. Immunocytochemical results indicated that μ‐crystallin was distributed within type II fibrocytes of the lateral wall, which are known to contain Na,K‐ATPase.

Conclusions

CRYM mutations may cause auditory dysfunction through thyroid hormone binding effects on the fibrocytes of the cochlea. μ‐Crystallin may be involved in the potassium ion recycling system together with Na,K‐ATPase. Future animal experiments will be necessary to confirm a causal relation between Na,K‐ATPase, T3, and deafness.     

Impact of MELD allocation policy on survival outcomes after liver transplantation: a single-center study in northeast Brazil

OBJECTIVE:

To analyze the impact of model for end‐stage liver disease (MELD) allocation policy on survival outcomes after liver transplantation (LT).

INTRODUCTION:

Considering that an ideal system of grafts allocation should also ensure improved survival after transplantation, changes in allocation policies need to be evaluated in different contexts as an evolutionary process.

METHODS:

A retrospective cohort study was carried out among patients who underwent LT at the University of Pernambuco. Two groups of patients transplanted before and after the MELD allocation policy implementation were identified and compared using early postoperative mortality and post‐LT survival as end‐points.

RESULTS:

Overall, early postoperative mortality did not significantly differ between cohorts (16.43% vs. 8.14%; p = 0.112). Although at 6 and 36‐months the difference between pre‐ vs. post‐MELD survival was only marginally significant (p = 0.066 and p = 0.063; respectively), better short, medium and long‐term post‐LT survival were observed in the post‐MELD period. Subgroups analysis showed special benefits to patients categorized as non‐hepatocellular carcinoma (non‐HCC) and moderate risk, as determined by MELD score (15‐20).

DISCUSSION:

This study ensured a more robust estimate of how the MELD policy affected post‐LT survival outcomes in Brazil and was the first to show significantly better survival after this new policy was implemented. Additionally, we explored some potential reasons for our divergent survival outcomes.

CONCLUSION:

Better survival outcomes were observed in this study after implementation of the MELD criterion, particularly amongst patients categorized as non‐HCC and moderate risk by MELD scoring. Governmental involvement in organ transplantation was possibly the main reason for improved survival.     

Array-CGH detection of micro rearrangements in mentally retarded individuals: clinical significance of imbalances present both in affected children and normal parents

Background

The underlying causes of mental retardation remain unknown in about half the cases. Recent array‐CGH studies demonstrated cryptic imbalances in about 25% of patients previously thought to be chromosomally normal.

Objective and methods

Array‐CGH with approximately 3500 large insert clones spaced at ∼1 Mb intervals was used to investigate DNA copy number changes in 81 mentally impaired individuals.

Results

Imbalances never observed in control chromosomes were detected in 20 patients (25%): seven were de novo, nine were inherited, and four could not have their origin determined. Six other alterations detected by array were disregarded because they were shown by FISH either to hybridise to both homologues similarly in a presumptive deletion (one case) or to involve clones that hybridised to multiple sites (five cases). All de novo imbalances were assumed to be causally related to the abnormal phenotypes. Among the others, a causal relation between the rearrangements and an aberrant phenotype could be inferred in six cases, including two imbalances of the X chromosome, where the associated clinical features segregated as X linked recessive traits.

Conclusions

In all, 13 of 81 patients (16%) were found to have chromosomal imbalances probably related to their clinical features. The clinical significance of the seven remaining imbalances remains unclear. The limited ability to differentiate between inherited copy number variations which cause abnormal phenotypes and rare variants unrelated to clinical alterations currently constitutes a limitation in the use of CGH‐microarray for guiding genetic counselling.     

Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities

Background

Subtelomere fluorescence in situ hybridisation (FISH) analysis has increasingly been used as an adjunct to routine cytogenetic testing in order to detect small rearrangements. Previous reports have estimated an overall abnormality rate of 6%, with a range of 2–29% because of different inclusion criteria.

Methods

This study presents data compiled from 11 688 cases referred for subtelomere FISH testing in three clinical cytogenetic laboratories.

Results

In this study population, the detection rate for clinically significant subtelomere abnormalities was approximately 2.5%, with an additional 0.5% detection of presumed familial variants. Approximately half of the clinically significant abnormalities identified were terminal deletions, the majority of which were de novo. Most of the remaining cases were unbalanced translocations between two chromosomes or two arms of the same chromosome. Approximately 60% of the unbalanced translocations were inherited from a parent carrying a balanced form of the rearrangement. Other abnormalities identified included tandem duplications, apparently balanced translocations, partial deletions, and insertions. Interestingly, 9 cases (0.08%) were found to have interstitial deletions of non‐telomeric control loci, either BCR on 22q or PML on 15q. The most common clinically significant imbalances found were deletions of 1p, 22q, 4p, 9q, 8p, 2q and 20p. The most common familial variants were a deletion or duplication of 10q, deletion of 4q, deletion of Yq, and duplication of X/Yp onto Xq.

Conclusions

This study of subtelomere rearrangements is a 20 fold increase in number over the previously reported largest study and represents an unbiased analysis of subtelomere rearrangements in a large, unselected patient population.     

Size bias of fragile X premutation alleles in late-onset movement disorders

Background

Fragile X‐associated tremor/ataxia syndrome (FXTAS), caused by premutation expansions (55–200 CGG repeats) of the FMR1 gene, shares clinical features with other movement disorders, particularly in the domains of gait ataxia, intention tremor and parkinsonism. However, the prevalence of FXTAS within other diagnostic categories is not well defined.

Methods

A meta‐analysis was conducted of all published (n = 14) genetic screens for expanded FMR1 alleles to assess the prevalence and CGG‐repeat size bias of FMR1 premutation alleles in those populations.

Results

In men with late‐onset cerebellar ataxia, the prevalence of premutation alleles (1.5%; 16/1049) was 13 times greater than expected based on its prevalence in the general population (2%; 16/818 for age of onset >50 years; odds ratio 12.4; 95% confidence interval 1.6 to 93.5). Meta‐analysis of CGG‐repeat data for screened patients with premutation alleles shows a shift to larger repeat size than in the general population (p<0.001). 86% (19/22) of premutation alleles were larger than 70 repeats in the patients screened, whereas only approximately 22% of premutation alleles are larger than 70 repeats in the general population.

Conclusions

Expanded FMR1 alleles contribute to cases of late‐onset sporadic cerebellar ataxia, suggesting that FMR1 genetic testing should be carried out in such cases. The biased distribution of FMR1 allele sizes has substantial implications for genetic counselling of carriers with smaller alleles who are at a low risk of developing FXTAS, and suggests that the estimated prevalence of FXTAS among men >50 years of age in the general population may be two to threefold lower than the initial figure of 1 in 3000.     

Entrapped victims in motor vehicle collisions: characteristics and prehospital care in the city of São Paulo, Brazil

OBJECTIVE:

To examine the severity of trauma in entrapped victims and to identify risk factors for mortality and morbidity.

INTRODUCTION:

Triage and rapid assessment of trauma severity is essential to provide the needed resources during prehospital and hospital phases and for outcome prediction. It is expected that entrapped victims will have greater severity of trauma and mortality than non‐entrapped subjects.

METHODS:

A transverse, case–control, retrospective study of 1203 victims of motor vehicle collisions treated during 1 year by the prehospital service in São Paulo, Brazil was carried out. All patients were drivers, comprising 401 entrapped victims (33.3%) and 802 non‐entrapped consecutive controls (66.7%). Sex, age, mortality rates, Glasgow Coma Scale (GCS), Revised Trauma Score (RTS), corporal segments, timing of the prehospital care and resource use were compared between the groups. The results were analysed by χ², Zres, analysis of variance and Bonferroni tests.

RESULTS:

Entrapped victims were predominantly men (84.8%), aged 32±13.1 years, with immediate mortality of 10.2% and overall mortality of 11.7%. They had a probability of death at the scene 8.2 times greater than that of non‐entrapped victims. The main cause of death was hemorrhage for entrapped victims (45.2%) and trauma for non‐entrapped victims. Of the entrapped victims who survived, 18.7% had a severe GCS (OR = 10.62), 12% a severe RTS (OR = 9.78) and 23.7% were in shock (OR = 3.38). Entrapped victims were more commonly transported to advanced life support units and to tertiary hospitals.

CONCLUSION:

Entrapped victims had greater trauma severity, more blood loss and a greater mortality than respective, non‐entrapped controls.     

Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports

Background

Chromosomal abnormalities are a major cause of mental retardation and multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been done by standard karyotyping. Previous array CGH studies on selected patients with chromosomal phenotypes and normal karyotypes suggested an incidence of 10–15% of previously unnoticed de novo chromosomal imbalances.

Objective

To report array CGH screening of a series of 140 patients (the largest published so far) with idiopathic MCA/MR but normal karyotype.

Results

Submicroscopic chromosomal imbalances were detected in 28 of the 140 patients (20%) and included 18 deletions, seven duplications, and three unbalanced translocations. Seventeen of 24 imbalances were confirmed de novo and 19 were assumed to be causal. Excluding subtelomeric imbalances, our study identified 11 clinically relevant interstitial submicroscopic imbalances (8%). Taking this and previously reported studies into consideration, array CGH screening with a resolution of at least 1 Mb has been undertaken on 432 patients with MCA/MR. Most imbalances are non‐recurrent and spread across the genome. In at least 8.8% of these patients (38 of 432) de novo intrachromosomal alterations have been identified.

Conclusions

Array CGH should be considered an essential aspect of the genetic analysis of patients with MCA/MR. In addition, in the present study three patients were mosaic for a structural chromosome rearrangement. One of these patients had monosomy 7 in as few as 8% of the cells, showing that array CGH allows detection of low grade mosaicisims.     

Biochemical screening of type I collagen in osteogenesis imperfecta: detection of glycine substitutions in the amino end of the alpha chains requires supplementation by molecular analysis

Background

The biochemical test for osteogenesis imperfecta (OI) detects structural abnormalities in the helical region of type I collagen as delayed electrophoretic migration of alpha chains on SDS‐urea‐PAGE. Sensitivity of this test is based on overmodification of alpha chains in helices with a glycine substitution or other structural defect. The limits of detectability have not been reported.

Methods

We compared the collagen electrophoretic migration of 30 probands (types III or IV OI) with known mutations in the amino half of the α1(I) and α2(I) chains. Differences in sensitivity were examined by 5% and 6% SDS‐urea‐PAGE, and with respect to alpha chain, location along the chain, and substituting amino acid.

Results

Sensitivity was enhanced on 5% gels, and by examination of intracellular and secreted collagen. In α1(I), substitutions in the first 100 residues were not detectable; 7% of cases in the current Mutation Consortium database are in this region. α1(I) substitutions between residues 100 and 230 were variably detectable, while those after residue 232 were all detected. In α2(I), variability of electrophoretic detection extended through residue 436. About a third of cases in the Consortium database are located in the combined variable detection region. Biochemical sensitivity did not correlate with substituting residue.

Conclusions

Complete testing of probands with normal type I collagen biochemical results requires supplementation by molecular analysis of cDNA or gDNA in the amino third of α1(I) and amino half of α2(I). Mutation detection in OI is important for counselling, reproductive decisions, exclusion of child abuse, and genotype‐phenotype correlations.     

Reduced penetrance alleles for Huntington's disease: a multi-centre direct observational study

Objective

To obtain penetrance data for Huntington''s disease when DNA results are in the range of 36–39 CAG repeats and assess the consistency of reporting the upper allele from two reference centres.

Method

Data were collected anonymously on age of onset or age last known to be unaffected from a cohort of individuals with results in this range. DNA samples were re‐analysed in two reference centres. Kaplan‐Meier analysis was used to construct an age of onset curve and penetrance figures.

Results

Clinical data and concordant DNA results from both reference centres were available for 176 samples; penetrance figures (and 95% confidence intervals) for this cohort, at age 65 and 75 years, were 63.9% (55.5% to 73.2%) and 74.2% (64.2% to 84.2%), respectively. Inclusion of 28 additional subjects for whom repeat DNA results were unavailable, obtained from only one reference centre, or discrepant by one repeat within this range, gave penetrance data (including 95% confidence intervals) at ages 65 and 75 years of 62.4% (54.4% to 70.4%) and 72.7.% (63.3% to 82.1%), respectively. 238 duplicate results were available from the reference centres; 10 (4.2%) differed by one CAG repeat in the reporting of the upper allele and in two (0.84%) of these cases the discrepancy was between 39 and 40 repeats.

Conclusion

When DNA results are in this range, a conservative approach is to say that there is at least a 40% chance the person will be asymptomatic at age 65 years and at least a 30% chance the person will be asymptomatic at age 75 years.     

The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management

Background

Mutations in the PTEN gene cause two disorders that predispose to cancer, Bannayan–Riley–Ruvalcaba and Cowden syndromes. Some patients with a PTEN mutation have only macrocephaly and autism, but they may still be at risk for neoplasms. Vascular anomalies occur in patients with a PTEN mutation, but they have not been systematically studied or precisely defined.

Method

We analysed the clinical and radiological features of the vascular anomalies in 26 patients with PTEN mutations who were either seen or had their medical records reviewed at Children''s Hospital Boston.

Results

All 23 patients who had their head circumference measured were macrocephalic, and all 13 male patients who were fully examined had penile freckling. Vascular anomalies were found in 14/26 (54%) of patients: 8/14 (57%) had multiple lesions and 11/13 (85%) who had cross‐sectional imaging had intramuscular vascular lesions. Radiographic studies showed that 12/14 (86%) were fast‐flow vascular anomalies, and angiography typically showed focal segmental dilatation of draining veins. Excessive ectopic fat in the vascular anomalies was present in 11/12 (92%) of patients on CT or MRI. Intracranial developmental venous anomalies (DVAs) were found in 8/9 (89%) of patients who had brain MRI with contrast.

Conclusions

Vascular anomalies in patients with a PTEN mutation are typically multifocal intramuscular combinations of fast‐flow channels and ectopic fat. Cerebral DVAs are very common. PTEN mutational analysis should be considered for all macrocephalic patients with fast‐flow vascular anomalies or multiple intracranial DVAs.     

Skewed X chromosome inactivation and early-onset breast cancer

Background

Skewed X chromosome inactivation may be more common in women with epithelial ovarian cancer and early‐onset breast cancer. We tested this hypothesis in a group of 235 breast cancer patients and 253 controls (mean age 45.8 years) from a larger population based case control study.

Methods

We measured X chromosome inactivation with the AR gene assay in lymphocyte DNA digested with the methylation specific enzyme HpaII. We judged skewness using an adjusted measure (relative to the undigested sample) with a cut point of 75%, and an unadjusted measure where skewed was defined as >90% of the signal from one allele in the HpaII digested sample.

Results

There were no significant differences in any of the skewing measures between cases and controls. Using the adjusted skewing measure among pre‐menopausal subjects under the age of 50, 14% of cases versus 11% of controls were skewed, OR = 1.2, 95% CI 0.6 to 2.3; using the unadjusted measure, OR = 0.9, 95% CI 0.4 to 2.0.

Conclusions

While we cannot rule out a subtle difference of approximately twofold or less, we have failed to find a significant difference in the prevalence of skewed X chromosome inactivation in younger women with breast cancer compared to controls.     

MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability

Background

Heritable alterations in CDKN2A account for a subset of familial melanoma cases although no robust method exists to identify those at risk of being a mutation carrier.

Methods

We set out to construct a model for estimating CDKN2A mutation carrier probability using a cohort of 116 consecutive familial cutaneous melanoma patients evaluated at Massachusetts General Hospital Pigmented Lesion Center between April 2001 and September 2004. Germline CDKN2A and CDK4 status on the familial melanoma cases and clinical features associated with mutational status were then used to build a multiple logistic regression model to predict carrier probability and performance of model on external validation.

Results

From the 116 kindreds prone to melanoma in the Boston area, 13 CDKN2A mutation carriers were identified and 12 were subsequently used in the modeling. Proband age at diagnosis, number of proband primaries, and number of additional family primaries were most closely associated with germline mutations. The estimated probability of the proband being a mutation carrier based on the logistic regression model (MELPREDICT) is given bywhere L = 1.99+[0.92×(no. of proband primaries)]+[0.74×(no. of additional family primaries)]−[2.11×ln_(age)]. The mean estimated probabilities for subjects in the Boston dataset were 55.4% and 5.1% for the mutation carriers and non‐carriers respectively. In a receiver operator characteristic analysis, the area under the curve was 0.881 (95% confidence interval 0.739 to 1.000) for the Boston model set (n = 116) and 0.803 (0.729 to 0.877) for an external Toronto hereditary melanoma cohort (n = 143).

Conclusions

These results represent the first‐iteration logistic regression model to approximate CDKN2A carrier probability. Validation of this model with an external dataset revealed relatively robust performance.     

Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes

Background

Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon‐sarcoglycan gene (SGCE) on chromosome 7q21.

Methods

We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M‐D), essential myoclonus (E‐M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested.

Results

Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M‐D and five E‐M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non‐carriers. None of the patients had severe psychiatric disorders.

Conclusion

This large cohort of index patients shows that SGCE mutations are primarily found in patients with M‐D and to a lesser extent E‐M, but are present in only 30% of these patients combined (M‐D and E‐M).