Factors influencing sib risks for multiple sclerosis

Multiple sclerosis (MS) is now thought to be a complex trait determined by genetic and non-genetic (environmental) factors. The study group, identified from the Canadian Collaborative Project on Genetic Susceptibility to MS, consisted of 1,083 MS index cases, 2,166 of their parents and 3,112 of their sibs. The results, together with those of a previous study on an independent data set, suggest that gender, age of MS onset and having one parent with MS may individually and interactively alter sib risks for MS. These data are important for genetic counselling and for molecular genetic (genome screens, candidate gene analyses) studies.     

Occurrence of childhood cancers among sibs and estimation of familial risks.

An analysis which includes the majority of the cases of childhood cancer occurring in Britain over a period of about 20 years suggests that there is a small familial element in the aetiology of these diseases; aggregations within sibships were observed more frequently than would be expected by chance. Possible explanations of these findings are considered. Some, perhaps many, of the cases within such sibships may be due to associations between malignant disease and various genetically determined conditions at a suclinical level or in the heterozygous state. Alternatively, the observed familial aggregations may be attributable to the fact that sibs share a common environment. Childhood cancer in twins is discussed and findings compared with those from the United States. Attention is drawn to a number of interesting combinations of tumours in sibs, particularly brain tumours and bone cancers. The implications of the findings for genetic counselling are discussed; it is emphasized that, though there appears to be an increased risk that sibs of children with malignant disease will also be affected by such diseases, this amounts overall only to a doubling of the general population risk. Whether or not the explanation is a genetic one, the actual magnitude of the risk for such sibs is only about 1 in 300.     

Multiple sclerosis. Updated risks for relatives

Two important characteristics of multiple sclerosis (MS) are familial clustering and a variable age of onset. There is increasing evidence for a genetically influenced susceptibility in MS. Because of this, patients and their relatives are increasingly asking about the risk for relatives of developing MS. In the MS Clinic in Vancouver, genetic histories are taken routinely for all patients and are updated annually. Patients do not attend the clinic specifically to participate in genetic studies, which could result in over-representation of familial cases. Data were available for 815 MS index cases and 11,345 of their relatives. Age-specific MS risks were calculated for first-, second-, and third-degree relatives of probands and are presented in an easy-reference format. In general, first-degree relatives of probands have a risk that is 30–50 times greater than the 0.1% risk for the general population.     

Recurrence risk figures for isolated tetralogy of Fallot after screening for 22q11 microdeletion.

Isolated tetralogy of Fallot (TF) has a multifactorial mode of inheritance in most cases, and recurrence risk rates of 2.5-3% have been attributed to first degree relatives of an affected child. In a subgroup of patients with a strong family history, the transmission of a monogenic trait has been suspected. Microdeletion 22q11 (del(22q11)) can cause TF in the setting of DiGeorge and velocardiofacial syndromes, and has also been related to familial conotruncal cardiac defects. Empirical risk figures in families after exclusion of del(22q11) have never been calculated. We have investigated the overall occurrence of congenital heart defect (CHD) in relatives of 102 patients with isolated non-syndromic TF previously screened for del(22q11). Our results show that the frequency of CHD is 3% in sibs, 0.5% in parents, 0.3% in grandparents, 0.2% in uncles or aunts, and 0.6% in first cousins. The recurrence risk rate for sibs in our series is the same as that previously estimated, indicating that after exclusion of patients with del(22q11) genetic counselling to patients with isolated TF should not be modified. A high concordance rate among our affected sibs has been documented. Gene(s) different from those located on chromosome 22q11 must be involved in causing familial aggregation of non-syndromic TF in these cases.     

Risk of recurrence after two children with central nervous system malformations in an area of high incidence.

This study was undertaken to provide an estimate of the recurrence risk of central nervous system (CNS) malformation in families with two or more affected children. The hospital records and the records of the Genetic Counseling Clinics were examined for instances where a child born between 1962 to 1973 had spina bifida and anencephalus and was documented as having an affected elder sib; such children were taken as index patients. Parents of 76 families with 89 index patients were interviewed. Fifty-one index patients had younger sibs; of 85 younger sibs, 12 had spina bifida and six anencephalus (1 in 4.7). Little variation was observed in the proportion of subsequent children affected with the type of lesion in the index patient and the affected older sib. Ten index patients with two older affected sibs had 14 subsequent sibs of whom four had a CNS malformation (1 in 3.5). For the purpose of genetic counselling it was suggested that the risk after two and three children with CNS malformations in Northern Ireland was 1 in 5 and 1 in 4, respectively.     

Psychosocial outcome following genetic risk counselling for familial colorectal cancer. A comparison of affected patients and family members

Few studies have reported prospective data on psychosocial outcomes after genetic counselling in families with suspected hereditary non-polyposis colorectal cancer (HNPCC). This prospective study examines the impact of multidisciplinary risk counselling on the psychosocial outcome of 139 affected cancer patients and 233 family members without cancer at risk for HNPCC. Participants completed questionnaires specific to HNPCC before and 8 weeks after attending the familial cancer clinic. Affected patients' levels of distress were closely related to their health status and exceeded that of unaffected individuals, as did worry regarding their relatives' risk. A significant reduction in general anxiety (Hospital Anxiety and Depression Scale), distress specific to familial CRC (Impact of Events Scale) and general cancer worry (Distress Hereditary Disorder) was demonstrated after counselling in both affected patients and unaffected individuals. Reduction in distress was more pronounced in affected patients given a high risk of HNPCC compared with those at intermediate risk. Among unaffected individuals, distress declined regardless of what clinical risk they were assigned. Their perceptions of risk and cancer-related threat declined, while confidence in effective surveillance increased. These results suggest the beneficial effects of multidisciplinary counselling even when high-risk information is conveyed. A patient's previous cancer experience is likely to contribute to clinically relevant distress (15% of those patients), indicating the need for appropriate counselling.     

Recurrence risks for congenital hydrocephalus

To assess the contribution of genetic factors to the etiology of congenital hydrocephalus and to establish empiric recurrence risks for use in genetic counseling, records were reviewed on all patients with this diagnosis seen from 1968 to 1977. A total of 205 patients with documented hydrocephalus were identified in whom a specific non-genetic etiology could not be established. Of the 205 patients, 88 (57 M, 31 F) had aqueductal obstruction, 77 (49 M, 28 F) had communicating hydrocephalus, 26 (8 M, 18 F) had the Dandy-Walker syndrome, and 14 (7 M, 7 F) had other anatomic lesions. The 205 patients had a total of 353 full siblings, five with hydrocephalus (1.4 %). Of these five, four were male siblings of male patients with aqueductal obstruction, suggesting that these patients constitute a subgroup at high risk of having a genetic disorder. The overall recurrence rate among siblings of this group was 6 % (12 % for male sibs), suggesting that up to 25 % of cases of aqueductal obstruction in males may be the result of an X-linked recessive disorder. The recurrence risk for siblings of other patients with hydrocephalus appears to be quite low.     

Offspring of patients with tracheo-oesophageal fistula

One previous study has shown that the proportion affected of sibs of index patients with tracheo-oesophageal fistula is low. The survivors of the first successful operations for tracheo-oesophageal fistula are now reaching adult life, thus making possible a preliminary estimate of the proportion affected of children of index patients. From the records of two London hospitals a list of 99 consecutive patients was compiled; they were alive after operation and not known to have died since. Of these, 7 were living abroad, 4 were not willing to co-operate, and 9 (alive when last seen at hospital and probably still living) were not traced. The families of the remaining 79 were visited.

Of the 79, 15 were found to have had children; 13 of these had the common type 3b oesophageal atresia (with a fistula between the trachea or main bronchus and lower segment of the oesophagus) and the other two probably had the same lesion. These 15 patients have so far had 28 children and only one had tracheo-oesophageal fistula (again type 3b).

The 79 patients had had 130 sibs, of whom one had oesophageal atresia (without fistula), 3 had neural tube defects, and 2 had pyloric stenosis.

The series, though small, already indicates that the proportion affected of children of patients is too small for the disorder in the parents to have been caused by a dominant mutation. For genetic counselling it is, perhaps, reasonable for the present to assume that the risk to children is similar to the risk for sibs and may not be more than 1%.

     

Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. German Working Group on Paediatric Nephrology (Arbeitsgemeinschaft für P?diatrische Nephrologie.

In a systematic study on the clinical picture and genetics of cystic kidneys in children, in association with the German working group on paediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie), we have investigated 79 children with early manifestation of autosomal dominant polycystic kidney disease (ADPKD). They belonged to 64 families (64 index patients and 15 affected sibs). Early manifestation was defined in this study as clinical symptoms (hypertension, proteinuria, impaired renal function, palpably enlarged kidneys) occurring before the age of 15 years. In order to estimate the recurrence risk to sibs of a previously diagnosed patient with early manifesting ADPKD, we found that 15 out of a total of 65 sibs of the 64 index patients (45% of the theoretically expected 32.5 gene carriers) showed comparable early manifestation. Another 10 symptom free children were diagnosed sonographically as having ADPKD before the age of 18 years, so that the total number of affected sibs was 25/65 in the study group, representing 76% of the gene carriers. Although the gene in childhood manifesting ADPKD can be transmitted through both sexes, a statistically significant (p < 0.05) maternal predominance was observed (M:F = 23:41). In affected sibs ages of onset, initial presentation, and the development of complications appeared to be similar in the majority of families. Our data indicate a high recurrence risk to sibs for early manifestation of ADPKD which has important implications for genetic counselling and clinical care of affected families and gives clues to the underlying genetic mechanism of childhood onset ADPKD.     

Intrafamilial variability in the clinical expression of familial hypercholesterolemia: importance of risk factor determination for genetic counselling

Kotze MJ, Davis HJ, Bissbort S, Langenhoven E, Brusnicky J, Oosthuizen CJJ. Intrafamilial variability in the clinical expression of familial hypercholesterolemia: importance of risk factor determination for genetic counselling.
Clin Genet 1993: 43: 295–299. © Munksgaard, 1993
A specific mutation in the low-density lipoprotein receptor (LDLR) gene causes familial hypercholesterolemia (FH) in about 60% of Afrikaner FH heterozygotes. Molecular diagnosis of this so-called FH Afrikaner-1 mutation was performed in a family with the disease. One individual did not develop coronary heart disease (CHD) by age 84, despite having the FH Afrikaner-1 mutation, while his son who inherited the same gene, developed CHD before age 50 and had to undergo bypass surgery. All the sibs in the third generation inherited the defective LDLR gene allele. This variation in clinical presentation creates a counselling dilemma. It also raises questions about the effect of diet and life style, and the possibility of other genes either contributing to the severity of the disease, or protecting against high lipid levels in plasma. An investigation of the influence of selected factors on the clinical expression of the FH Afrikaner-1 mutation in this family indicated that it was especially the elevated apolipoprotein (a) levels, in addition to low levels of high density lipoprotein cholesterol and raised triglyceride and apolipoprotein B levels, that were associated with a greater risk of developing CHD. These findings are thus in accordance with the view that the severity of CHD in FH patients is not only determined by the nature of the gene defect, but is also influenced by other risk factors.     

A family study of bladder exstrophy.

The families of 102 index patients with bladder exstrophy treated at The Hospital for Sick Children, Great Ormond Street were studied in an attempt to arrive at an empirical risk of recurrence for sibs. Of the 102 patients, 89 had complete exstrophy, eight had partial exstrophy (variant), and five had exstrophy of the cloaca. In all they had 162 sibs, none of whom had bladder exstrophy. The risk to sibs, in this study and from reports by surgeons of sib pairs in their consecutive series, is low and probably less than 1%. There is a suggestion of an increase in central nervous system malformation in sibs as well as in the index patients.     

PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism

The renal-coloboma syndrome (RCS, MIM 120330) is an autosomal dominant disorder caused by PAX2 gene mutations. We screened the entire coding sequence of the PAX2 gene for mutations in nine patients with RCS. We found five heterozygous PAX2 gene mutations: a dinucleotide insertion (2G) at position 619 in one sporadic RCS case, a single nucleotide insertion (619 + G) in three unrelated cases, and a single nucleotide deletion in a familial case. In this familial case, three affected sibs showed a striking ocular phenotypic variability. Each of the sibs carried a 619insG mutation, whilst unaffected parents did not, suggesting the presence of germline mosaicism. Interestingly, the 619insG mutation has been previously reported in several patients and is also responsible for the Pax21Neu mouse mutant, an animal model of human RCS. This study confirms the critical role of the PAX2 gene in human renal and ocular development. In addition, it emphasises the high variability of ocular defects associated with PAX2 mutations ranging from subtle optic disc anomalies to microphthalmia. Finally, the presence of PAX2 germline mosaicism highlights the difficulties associated with genetic counselling for PAX2 mutations.     

Genetic study of congenital heart defects in Northern Ireland (1974-1978).

Congenital heart defects are a major congenital abnormality and are assuming increasing importance. A study was undertaken to estimate the incidence of congenital heart defects in Northern Ireland over a five year period (1974-1978), to determine the age at diagnosis and to assess the risk of recurrence in sibs. An incidence rate of 7.3 per 1000 total births was found. This reduced to 3.1 per 1000 total births if only invasive methods of diagnosis (catheter studies, surgery, or necropsy) were considered. The overall risk of recurrence for sibs (excluding index patients with chromosomal abnormalities and syndromes) was 3.1%. In addition, excluding families with an affected parent and child gave a recurrence risk of 2.6%. By 6 weeks of age 63% of index patients had been diagnosed and this figure had risen to 88% by 1 year. This has important implications for studies which include only congenital heart defects diagnosed in the first year of life. Of 388 patients with a congenital heart defect confirmed by invasive criteria, 96 (24.7%) were found to have an extracardiac abnormality (ECA). Excluding those with epilepsy or mental handicap as the sole ECA left 91 (23.5%) with an ECA. This highlights the importance of looking for other abnormalities in a child with a congenital heart defect. The 388 index patients had 952 sibs of whom 72 (7.6%) had an ECA. Excluding those with minor abnormalities (inguinal hernias, undescended testes) as the sole ECA left 62 (6.5%) with a major ECA. In addition, excluding those with epilepsy or mental handicap as the sole ECA left 51 (5.4%) with a major ECA. Since parents are often reassured after the birth of a child with a congenital heart defect that their risk of having a child with a noncardiac abnormality is no greater than the general population this finding has important implications for genetic counselling.     

Men in breast cancer families: a preliminary qualitative study of awareness and experience.

In inherited forms of breast cancer, attention in clinical genetics services has focused on women because they are most at risk of developing cancer. Men at risk of transmitting a predisposing gene mutation are less likely to have a genetic test than the women in these families. This preliminary study investigates the perspective of the brothers of women with familial breast cancer and is based on qualitative analysis of 22 semistructured interviews using an attenuated form of Grounded Theory. There is an awareness among these men (without having had genetic counselling) that the breast cancer in their families is inherited. Some of them harbour fear of developing cancer themselves and many are concerned that their daughters might develop breast cancer. Some appeared to use avoidance as a coping strategy. The men were very often excluded from family conversations about breast cancer. Implications for the provision of genetic counselling for these families are discussed.     

Familial congenital diaphragmatic defects: Aspects of etiology,prenatal diagnosis,and treatment

We present 14 familial cases from five Finnish families affected with a life-threatening congenital diaphragmatic defect (CDD) and review data on 53 previously published familial cases. CDD occurred in three sibs and their half brother's son, and probably in all four offspring of parents consanguineous as both first and second cousins. In the remaining three Finnish families and in the vast majority of the previously reported familial cases, only two sibs were affected. Two thirds of those affected were males both in the Finnish and the overall series. Pedigree data, delayed fusion of the diaphragm as the primary pathogenetic mechanism, varying anatomical structure of the defective hemidiaphragm, association with other congenital anomalies, and data on animal experiments are more in accordance with multifactorial determination than with recessive inheritance. This does not exclude other genetic causes in some familial cases. The recurrence risk for sibs after one affected sib is about 2%. As the prognosis, especially in familial cases of CDD has remained grave, the development of fetal surgical treatment is desirable. This emphasizes the future role of prenatal diagnosis by ultrasound.     

Multiple sclerosis: updated risks for relatives

Two important characteristics of multiple sclerosis (MS) are familial clustering and a variable age of onset. There is increasing evidence for a genetically influenced susceptibility in MS. Because of this, patients and their relatives are increasingly asking about the risk for relatives of developing MS. In the MS Clinic in Vancouver, genetic histories are taken routinely for all patients and are updated annually. Patients do not attend the clinic specifically to participate in genetic studies, which could result in over-representation of familial cases. Data were available for 815 MS index cases and 11,345 of their relatives. Age-specific MS risks were calculated for first-, second-, and third-degree relatives of probands and are presented in an easy-reference format. In general, first-degree relatives of probands have a risk that is 30-50 times greater than the 0.1% risk for the general population.     

Empirical recurrence risk after unidentified multiple congenital abnormalities.

Thirty-five fetal deaths (30.4%) and 12 cases of congenital abnormality (15.0%) occurred in 117 subsequent pregnancies and 80 sibs of 112 consultands who had babies with unidentified multiple congenital abnormalities after genetic counselling. The specific recurrence risk of unidentified multiple congenital abnormalities was 5%.     

Familial recurrence rates and genetic models of multiple sclerosis

Susceptibility to multiple sclerosis (MS) is determined by both inherited and non-inherited factors. The importance of genetic factors is demonstrated by the increased risk of disease in relatives of MS patients. Our objective was to determine the implications of the observed familial recurrence risks for the genetic basis of MS. We developed a computer program which calculates recurrence risks for monozygotic (MZ) twins, siblings, and second degree relatives, and used it to calculate recurrence risks for a wide variety of genetic models. We investigated models with different numbers of genes, different patterns of interaction between the genes, and dominant or recessive inheritance. The models that best reproduced the observed values had multiple loci with strongly synergistic interaction and autosomal dominant (AD) inheritance. At least six loci were required, and we found no upper limit on the number of loci. Models with genetic heterogeneity, where only a fraction of the risk loci are required for disease, are possible. In models with large numbers of loci the "abnormal" alleles conferring risk of disease are the most common allele. We conclude that a variety of genetic models with multiple genes, dominant inheritance, and synergistic interaction between risk genes are consistent with the observed familial recurrence rates in MS.     

Holoprosencephaly: variation of expression in face and brain in three sibs.

A family is described containing three sibs with holoprosencephaly. They showed a striking diversity of both cerebral and facial abnormalities. Autosomal recessive inheritance seems most likely. Because of the great variety in expression of this disorder, it is of importance for genetic counselling to examine both sibs and parents.     

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.