Expanding the genotypic spectrum of Perrault syndrome.

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome.

Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q.

Holt-Oram syndrome (HOS) is an autosomal dominant condition affecting the heart and upper limbs. We have sought to identify the location of this gene using microsatellite DNA markers in a linkage study. Of seven families analysed, five show linkage between HOS and markers on chromosome 12q. But the two remaining families, phenotypically indistinguishable from the others, do not show this linkage. Analysis with the computer program HOMOG indicates that HOS is a heterogeneous disease. Our analysis places one HOS locus in a 21 cM interval in the distal region of chromosome 12q. The localization of a gene for HOS, reported here, represents an important step towards a better understanding of limb and cardiac development.

Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family.

Holt-Oram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mouse Tbx5 gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a premature stop codon in the TBX5 gene product. Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development.

Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth.

OBJECTIVE: Barth Syndrome (BTHS) is an X-linked multisystem disorder (OMIM 302060) usually diagnosed in infancy and characterized by cardiac problems [dilated cardiomyopathy (DCM) ± endocardial fibroelastosis (EFE) ± left ventricular non-compaction (LVNC)], proximal myopathy, feeding problems, growth retardation, neutropenia, organic aciduria and variable respiratory chain abnormalities. We wished to determine whether BTHS had a significant impact on fetal and perinatal health in a large cohort of family groups originating from a defined region. METHOD: Case note review on 19 families originating from the UK and known to the Barth Syndrome Service of the Bristol Royal Hospital for Children. RESULTS: Details are presented on six kindreds (32%) with genetically and biochemically proven BTHS that demonstrate a wider phenotype including male fetal loss, stillbirth and severe neonatal illness or death. In these families, 9 males were stillborn and 14 died as neonates or infants but there were no losses of females. BTHS was definitively proven in five males with fetal onset of DCM ± hydrops/EFE/LVNC. CONCLUSION: These findings stress the importance of considering BTHS in the differential diagnosis of unexplained male hydrops, DCM, EFE, LVNC or pregnancy loss, as well as in neonates with hypoglycemia, lactic acidosis and idiopathic mitochondrial disease.

De novo variants in CNOT3 cause a variable neurodevelopmental disorder.

As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.

OBJECTIVE: To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. METHODS: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. RESULTS: Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett-like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. CONCLUSIONS: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.

Inherited pericentric inversion (X)(p11.4q11.2) associated with delayed puberty and obesity in two brothers.

We report two brothers with hypogonadotropic hypogonadism (HH), obesity and short stature associated with a maternally inherited pericentric inversion (X)(p11.4q11.2). On the basis that either breakpoint might disrupt a gene whose function is critical to normal sexual development we mapped the chromosomal breakpoints using two-colour fluorescent in situ hybridisation (FISH). The position of both the Xp11.4 and Xq11.2 breakpoints was refined using a panel of ordered BAC clones. No known genes were shown to map to the breakpoint regions. While we cannot entirely exclude the possibility that association between the clinical and cytogenetic phenotypes in the family is coincidental, it is possible that the inversion is responsible for HH through alternative molecular mechanisms such as position effects.

Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy.

We have recently shown that Okihiro syndrome results from mutation in the putative zinc finger transcription factor gene SALL4 on chromosome 20q13.13-13.2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome. We analysed further families/patients with the clinical diagnosis of Holt-Oram syndrome and acro-renal-ocular syndrome for SALL4 mutations. We identified a novel SALL4 mutation in one family where the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. We also found two novel mutations in two German families originally diagnosed as Holt-Oram syndrome and a further mutation in one out of two families carrying the diagnosis acro-renal-ocular syndrome. Our results show that some cases of "thalidomide embryopathy" might be the result of SALL4 mutations, resulting in an increased risk for similarly affected offspring. Furthermore we confirm the overlap of acro-renal-ocular syndrome with Okihiro syndrome at the molecular level and expand the phenotype of SALL4 mutations.

Thrombocytopenia-absent radius syndrome: a clinical genetic study.

The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified.

Multilevel investigation of variation in HoNOS ratings by mental health professionals: a naturalistic study of consecutive referrals.

Episodes of mental healthcare in specialist psychiatric services often begin with the assessment of clinical and psychosocial needs of patients by healthcare professionals. Particularly for patients with complex needs or severe problems, ratings of clinical and social functioning at the start of each episode of care may serve as a baseline against which subsequent measures can be compared. Currently, little is known about service variations in such assessments on referrals from primary care. We set out to quantify variability in initial assessments performed by healthcare professionals in three CMHTs in Bristol (UK) using the Health of the Nation Outcome Scales (HoNOS). We tested the hypothesis that variations in HoNOS total and sub-scale scores are related to referral source (general practices), healthcare assessor (in CMHTs) and the assessor's professional group. Statistical analysis was performed using multilevel variance components models with cross-classified random effects. We found that variation due to assessor substantially exceeded that due to referral source (general practices). Furthermore, patient variance differed by assessor profession for the HoNOS--Impairment scores. Assessor variance differed by assessor profession for the HoNOS--Social scores. As HoNOS total and subscale scores show much larger variation by assessor than by referral source, investigations of HoNOS scores must take assessors into account. Services should implement and evaluate interdisciplinary training to improve consistency in use of rating thresholds; such initiatives could be evaluated using these extensions of multilevel models. Future research should aim to integrate routine diagnostic data with continuous outcomes to address selection effects (of patients to assessors) better.

Simultaneous modelling of time trends and regional variation in mortality rates.

BACKGROUND: We seek to model the regional component of the variance in the mortality rates in the UK and to ascertain if there is evidence that this regional variance is increasing in recent periods. METHODS: Age Period Cohort (APC) models, based on the local 'curvatures', are used in each region to describe the changes in the trends in the mortality rates. This is extended to a multilevel model to estimate the regional component of the variance in the rates and to estimate the effect of regional differences in the trends in the rates. We show how the use of a multilevel APC model can help to distinguish the cohort and period trends in the mortality rates from the cohort and period effects on the regional variance in these rates. RESULTS: For both sexes, but particularly for females, a reduction in the rate of decrease in mortality was found around 1960. In addition, particularly for females, cohorts born after 1930 appear to show reductions in mortality at an increased rate. It is demonstrated that there is evidence that the between-region variation in the rates has not remained constant and that it is much less now than it was at the beginning of the data series. Further, there is evidence that the trends in the rates are not the same in all regions and that while there is a convergence of the rates in many regions, Scotland, in particular, stands out as a region which contributes most to the regional variation in mortality rates. CONCLUSION: Evidence of regional variation in mortality rates has been found with a suggestion of a decrease over the period of the study though with some stability since 1951.

Family and friends' influences on the uptake of regular smoking from mid-adolescence to early adulthood.

AIMS: To examine the effect of family and friends' smoking on uptake of regular smoking among young people from mid-adolescence to early adulthood; whether such effects are time limited, vary by social class and gender, and the extent to which uptake precedes or follows friends' smoking. SETTING: The West of Scotland. DESIGN AND PARTICIPANTS: A longitudinal survey of 1009 15-year-olds interviewed at baseline, followed-up at 16, 18, 21 and 23 years of age, using interviews and postal questionnaires. MEASUREMENTS: Self-reported measures of smoking were used, allowing analysis of the uptake of regular smoking (1 + cigarette per day) between 15 and 23, and in the periods 15-16, 16-18 and 18-21 years. Measures of parental and sibling smoking and social class were obtained at baseline and respondents' reports of friends' smoking at 15 and 18 years. FINDINGS: Regular smoking more than doubled between 15 (14%) and 23 (36%). Adjusted for other factors, no independent effect of parental smoking on uptake in any period was observed, an effect of sibling smoking being confined to uptake between 15 and 16. Friends' smoking at 15 increased the likelihood of uptake up to 10 times over the next year, but did not extend to later years; that at 18 increased it up to three times between 18 and 21. These effects did not vary by gender or social class. Further analysis revealed a strong effect of friends' smoking at age 18 on earlier as well as later uptake. CONCLUSIONS: Contrasting with prevalent assumptions, the period from mid-adolescence to early adulthood is important for uptake of regular smoking, and in particular reveals friends' smoking to be of continuing significance, especially around school-leaving when friendship networks often change markedly.

Sampling Asian minorities to assess health and welfare.

STUDY OBJECTIVE: The aims were (1) to sample a specified subgroup of the Asian minority; (2) to give proper representation to those outside the areas of concentration; and (3) to evaluate the costs and benefits of the method. DESIGN: Glasgow postcodes with varying concentrations of Asians were sampled, and 173 Asians aged 30-40 were interviewed after household screening of 1439 Asian names identified on the electoral roll or valuation roll. Areas with few Asians, and households with two or more members aged 30-40, were undersampled, and then reweighted. MEASUREMENTS AND MAIN RESULTS: Nurse measures of blood pressure, lung function, and body mass were taken, and selected interview measures of health and social background are reported. Substantial differences in blood pressure, reported health, and social background were revealed between Asians in areas of concentration and those in areas of dispersion. Loss in effective sample size due to undersampling and reweighting was 4-5% in the case of the area sampling, 13% in the case of the household sampling. Losses of potential sample members through under registration were probably less than 6%. CONCLUSIONS: The present sampling method targets subgroups successfully, and improves on sampling in areas of concentration, in that it enables dispersed members of the minority, who differ in crucial indices of health and social position, to be represented. The costs of the method are acceptable.

Mortality in Glasgow and Edinburgh: a paradigm of inequality in health.

STUDY OBJECTIVE: The aim was to describe, predict, and interpret mortality in Glasgow and Edinburgh. DESIGN: The study was an analysis of all cause and cause specific mortality data for quinquennia based on census years between 1931 and 1981, linking age and sex specific mortality rates by year of birth, for people dying between the ages of 25 and 74 years. SETTING: Glasgow and Edinburgh, Scotland. MAIN RESULTS: Age and sex specific mortality rates declined steadily in Edinburgh and Glasgow during the period 1931-1981, with rates always being lower in Edinburgh than in Glasgow. Since 1961 log mortality rates have tended to rise linearly with age in both cities. In 1979-83, the population of Glasgow reached a given all cause mortality rate 3.9 years earlier in men and 3.6 years earlier in women than did the population of Edinburgh. These differences have increased, and are predicted to increase further, especially in men. CONCLUSIONS: The current 40% cross sectional difference in mortality rates between the cities is largely determined by levels of mortality in early adulthood which provide a baseline for the subsequent rise in log mortality. Disease specific epidemiology provides a limited view of inequalities in health, and a partial basis for health promotion. Campaigns to alter disease risk profiles in adults should be complemented by measures operating earlier in life to reduce susceptibility to risk. Maternal and child health require greater priority in public health policy, particularly in areas of socioeconomic disadvantage.

Has regional variation in mortality rates declined since 1931, and in all age groups, in Britain? A re-analysis using formal statistical modelling.

STUDY OBJECTIVE: To examine changes in regional variance in all cause mortality rates in Great Britain from 1931-91 using formal statistical modelling procedures, and to follow up the suggestion by Illsley and Le Grand that there has been a reduction over time in the regional variance in younger but not older age groups. DESIGN, SETTING, AND PARTICIPANTS: Data were the age and sex specific death rates around each census from 1931-91 for the British regions, reconstructed to make them comparable with the 1981 regional definitions. Regional variance was modelled using bootstrap simulation tests and by age-period and age-cohort models. MEASUREMENTS AND MAIN RESULTS: While there was some evidence of a decline and levelling off of the regional variance over time in older age groups (over 35), the decline in younger age groups was more marked. This broadly confirms previous findings. Parametrising the period effect into linear and quadratic components, with allowance for an increase in regional variance in the war years, gave broadly comparable fit to the data as a model with period as a factor. Models for the changes in regional variance which were based on period effects seemed to provide a better description of the observed variances than those based on birth cohort effects. In the younger (but not older) groups there was evidence of a rise in the regional variance between 1981 and 1991. CONCLUSIONS: The decline in regional variance is larger in younger than in older age groups when allowance is made for the increase in regional variance over the war years. Statistical modelling can provide insights into the data which are not always detected by descriptive analyses. Moreover, they provide a capacity for generalisation beyond the particular data; relationships found can form the basis for studies of replicability, for example, in other countries.

Correlates of blood pressure in 15 year olds in the west of Scotland.

STUDY OBJECTIVE: The aim was to examine social and physical correlates of blood pressure in 15 year olds. DESIGN: This was the first, baseline, sweep of a longitudinal survey of 15 year olds based on a two stage stratified clustered random sample. SETTING: The Central Clydeside Conurbation, in the West of Scotland. In 1981 this had a population of 1.7 million and a standardised mortality ratio (relative to Scotland as a whole) of 109. SUBJECTS: A random sample of households containing 15 year olds were approached by Strathclyde Regional Council; 70% agreed to have their names passed on to the MRC (15% refused, 10% could not be contacted, and 5% had moved). Of these 1177, 11% refused to participate, 3% were not contactable/had moved, and 4% did not provide full data. Complete blood pressure data are available for 959 15 year olds (464 males and 495 females). MEASUREMENTS AND MAIN RESULTS: Blood pressure, pulse rate, height, weight, and room temperature were measured by nurses in the subjects' homes. Smoking, drinking, and frequency of vigorous exercise were self reported. Maternal height, birthweight, occupation of head of household, and housing tenure were reported by parents. After controlling for the other variables, systolic blood pressure was significantly associated with weight, pulse rate, and room temperature in males and with weight, pulse rate, housing tenure, smoking, and exercise in females. Diastolic blood pressure was associated with room temperature in males and with mother's height, pulse rate, and housing tenure in females. Controlling for current weight, birthweight was inversely related to systolic blood pressure in males and positively associated in females, though in neither case were these associations statistically significant. CONCLUSIONS: In males, blood pressure was mainly related to anthropometric factors whereas in females it was additionally related to socioeconomic and behavioural variables. Although not reaching significance, the weight standardised relationship between birthweight and systolic blood pressure was consistent for males, but not females, with those reported by recent British studies of children and adults. The longitudinal design of this study will allow us to examine correlates of blood pressure in the same individuals as they reach social and physical maturity.

Mesenteric angina complicating a mesodermal anomaly.

A child with macrocephaly-cutis marmorata developed severe abdominal pain thought to represent mesenteric angina. There were abnormalities of the aortic and mesenteric vasculature not previously reported in this condition. Angina therapy afforded amelioration of his symptoms. Mesenteric angina should be considered as a cause for abdominal pain in children with mesodermal anomalies.

Mortality variations in England and Wales between types of place: an analysis of the ONS longitudinal study. Office of National Statistics.

This study investigates the extent to which individuals, in England and Wales, in different types of place experience differential mortality once account is taken of personal (individual and household) social circumstances. Data comes from the Longitudinal Study of England and Wales of the Office of National Statistics, the respondents being a one percent national random sample of people aged between 25 and 74 at the 1971 census, followed until the end of 1985. For males and females separately, differences in mortality are found for the 36 types of Craig-Webber classification in models which include, at the individual level, a number of demographic and socio-economic variables (women being classified by their own occupation). In general, for both males and females, the same types of place have elevated or lowered mortality. For males a (cross-level) interaction exists between the proportion in the area in professional social classes and individual social class, the effects of individual social class being larger in areas containing a higher proportion of those in professional occupations. For females mortality is negatively related to the proportion of car-ownership in the area.

Reporting by parents of longstanding illness in their adolescent children.

Parents' proxy reports of longstanding illness in their 15 year children are compared with the young people's own reports, both overall and between different reporting contexts; mother alone, father alone and both parents together. Parents over-report longstanding, but not limiting longstanding, illness in comparison to self report. There is no evidence of differential over-reporting by reporting context, but a number of differences are found in the likelihood of disagreement between these reporting contexts. The gender of the young person influences the relationship between proxy and self reports.

Income and health: what is the nature of the relationship?

The aim of this article is to examine the relationship between income and morbidity, both before and after controlling for other socio-economic variables. We use data from the Health and Lifestyle Survey (first wave), a national sample survey of adults, aged 18 upwards, in England, Wales and Scotland, conducted in 1984-1985. In total, 9003 interviews were achieved. We examine the shape of the relationship between household equivalised income and height, waist-hip ratio, respiratory function (FEV1), malaise, limiting longterm illness. These indices of morbidity, both self-reported and measured, are approximately linearly related to the logarithm of income, in all except very high and low incomes (this means that increasing income is associated with better health, but that there are diminishing returns at higher levels of income). A doubling of income is associated with a similar effect on health, regardless of the point at which this occurs, providing this is within the central portion (10-90%) of the income distribution. The effect of income on the health measures is comparable to that of the other socio-economic variables in combination. The shape of the relationship found between income and health is compatible with worse health in countries with greater income inequality, without the need to postulate any direct effect of income inequality itself.