Non-affected Parents Research Articles

Family Analysis of Linkage and Association of HLA-DRB1, CTLA4, TGFB1, IL4, CCR5, RANTES, MMP9 and TIMP1 Gene Polymorphisms with Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Proteins of the immune system, as well as proteins that are involved in the infiltration of activated immune cells in the CNS, play an important role in the pathogenesis of MS. We investigated the association and linkage with MS of the following immune-system genes polymorphisms: HLA-DRB1,CTLA4,TGFB1,IL4,CCR5 andRANTES, as well as of the matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinase 1 (TIMP1) genes polymorphisms. For this purpose we used the transmission disequilibrium test (TDT). The group investigated was comprised of 100 nuclear families of Russian ethnicity, each consisting of an affected offspring and his nonaffected parents. It was found that HLA-DRB1*15alleleandMMP9*-1562C allele were transmitted from healthy heterozygous parents to affected children more frequently than alternative alleles (p = 0.02 andp = 0.04, respectively). Another family-based method, AFBAC (affected family-based control), showed MS association with HLA-DRB1*15, but not with theMMP9*-1562C allele.

The role of recollection in source memory: An examination of schizophrenia patients and their first-degree relatives

Source recognition memory deficits have repeatedly been observed in people with schizophrenia (SZ), and have also recently been observed in their first-degree relatives. These deficits have been hypothesized to result, at least in part, from impairments in the conscious recollection process. Although other processes are clearly also affected in SZ, it has been proposed that impairments in the conscious recollection process could be a parsimonious explanation for the source memory deficits observed in their relatives.Here, we tested 25 patients with SZ and 34 of their non-affected parents, as well as two groups of matched healthy controls, on a short-term associative memory task that shares the characteristics of standard source recognition tasks but minimizes the need for recollection of stored information from memory. This task was administered in order to determine if deficits can still be observed in these people when involvement of the conscious recollection process is minimized.We observed deficits on our short-term source memory task in people with SZ, but their first-degree relatives did not share this deficit. These results support the idea that multiple memory processes supporting associative/source memory are affected in SZ, whereas the source memory deficits previously observed in relatives of SZ seem specific to tasks that rely on the conscious recollection process.

A double hit implicates DIAPH3 as an autism risk gene

Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a 'double-hit' compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.

Significance of morphological features in schizophrenia of a Chinese population

Neuro-developmental hypothesis suggests that schizophrenia is originated from aberrant brain development during first and/or early trimester of gestation. Accordingly, when a schizophrenia gene is involved in the regulation of embryonic development and continues to play a role in the later life, it may result in the co-occurrence of defective organ systems and/or physiological functions with schizophrenia. We proposed a checklist with 13 morphological features and examine their prevalence rates in 151 schizophrenic patients and 151 controls. Statistical analyses showed that single transverse palmar crease, head circumference, covered epicanthus, finger length difference, and inner canthus distance, made significant contributions to schizophrenia. To rule out the age confounding effects on morphological features, we dropped older schizophrenic subjects and younger controls in further regression analysis. The regression model correctly classified 82.8% of control subjects (specificity) and 86.4% of schizophrenic patients (sensitivity), and provided an overall successful classification rate of 84.5%, with single transverse palmar crease on the first rank. The association of morphological features and schizophrenia is probably genetic in origin, as specific morphological features were more frequent in non-affected parents with higher genetic loading of schizophrenia. In addition, the association of finger length difference in schizophrenia found in this study has never been reported elsewhere. Our study showed that five out of 13 morphological features in the propose checklist may be used as biomarkers for schizophrenia, either for clinical practice or research purposes.

Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation

Chromosomal imbalances are the major cause of mental retardation (MR). Many of these imbalances are caused by submicroscopic deletions or duplications not detected by conventional cytogenetic methods. Microarray-based comparative genomic hybridization (array-CGH) is considered to be superior for the investigation of chromosomal aberrations in children with MR, and has been demonstrated to improve the diagnostic detection rate of these small chromosomal abnormalities. In this study we used 1 Mb genome-wide array-CGH to screen 48 children with MR and congenital malformations for submicroscopic chromosomal imbalances, where the underlying cause was unknown. All children were clinically investigated and subtelomere FISH analysis had been performed in all cases. Suspected microdeletion syndromes such as deletion 22q11.2, Williams-Beuren and Angelman syndromes were excluded before array-CGH analysis was performed. We identified de novo interstitial chromosomal imbalances in two patients (4%), and an interstitial deletion inherited from an affected mother in one patient (2%). In another two of the children (4%), suspected imbalances were detected but were also found in one of the non-affected parents. The yield of identified de novo alterations detected in this study is somewhat less than previously described, and might reflect the importance of which selection criterion of patients to be used before array-CGH analysis is performed. However, array-CGH proved to be a high-quality and reliable tool for genome-wide screening of MR patients of unknown etiology.

HYPEREKPLEXIA CAUSED BY DOMINANT-NEGATIVE SUPPRESSION OF GLYRA1 FUNCTION

Hyperekplexia (HE; startle disease; OMIM#149400) is a rare inheritable neurologic disorder characterized by an exaggerated response to sudden stimuli, muscular rigidity, and hyperreflexia, leading to chronic injuries due to unprotected falls. All symptoms are present at birth but gradually decline during the first year of life, although an exaggerated startle response remains during adulthood.1 Dysfunctional inhibitory neurotransmission by glycine (Gly) plays a central role in HE pathogenesis. All patients with HE carry mutations in genes encoding either for α1 (GLYRA1) or β (GLYRB) Gly receptor subunits, presynaptic Gly transporters (SLC6A5), or proteins involved in Gly receptor (GLYR) clustering, such as gephyrin (GPHN) and collybistin (ARHGEF9).1,2 GLYRA1 subunits interact in a heteropentameric complex with homologous β subunits (3α12β). Each subunit comprises an extracellular N-terminus, four α-helical transmembrane segments (TM1 to TM4), and an extracellular C-terminus; TM2 segments are thought to align the Cl− selective pore.1 Different GLYRA1 missense and nonsense mutations have been associated with autosomal dominant, autosomal recessive, and sporadic forms of HE. Missense mutations may show incomplete penetrance and impair channel gating, trafficking, and stability.3 Nonsense mutations have been reported only in recessive cases, in compound heterozygosity with a missense mutation, or in homozygosity in the offspring of consanguineous nonaffected parents and appear unable to cause the startle phenotype in heterozygosis.4,5 A recessive form of HE linked to a GLYRA1 null allele has been described,6 suggesting a nonpathogenic role for haplotype insufficiency. In this study, we investigated the functional consequences of a de novo …

Brain anatomy in non-affected parents of autistic probands: a MRI study

Autism is a neurodevelopmental disorder with an estimated genetic origin of 90%. Previous studies have reported an increase in brain volume of approximately 5% in autistic subjects, especially in children. If this increase in brain volume is genetically determined, biological parents of autistic probands might be expected to show brain enlargement, or at least intracranial enlargement, as well. Identifying structural brain abnormalities under genetic control is of particular importance as these could represent endophenotypes of autism. Using quantitative anatomic brain magnetic resonance imaging, volumes of intracranial, total brain, frontal, parietal, temporal and occipital lobe, cerebral and cortical gray and white matter, cerebellum, lateral ventricle, and third ventricle were measured in biological, non-affected parents of autistic probands (19 couples) and in healthy, closely matched control subjects (20 couples). No significant differences were found between the parents of the autistic probands and healthy control couples in any of the brain volumes. Adding gender as a factor in a second analysis did not reveal a significant interaction effect of gender by group. The present sample of biological, non-affected parents of autistic probands did not show brain enlargements. As the intracranium is not enlarged, it is unlikely that the brain volumes of the parents of autistic probands have originally been enlarged and have been normalized. Thus, increased brain volume in autism might be caused by the interaction of paternal and maternal genes, possibly with an additional effect of environmental factors, or increased brain volumes might reflect phenotypes of autism.

Effects of coresidence and caregiving on health of Thai parents of adult children with AIDS.

To explore potential effects on the health of older parents living with and caring for people infected with HIV. Comparison of health outcomes between affected parents and matched nonaffected parents, and between principal caregivers and nonprincipal caregivers in Thailand. Survey data from 394 affected households and 376 nonaffected households; qualitative data from 18 interviews of affected older parents. A large proportion of older people with HIV-infected children provided time-consuming and strenuous caregiving services to them. Mothers shouldered most of this burden. Mothers who had a child die from AIDS reported lower levels of overall happiness than did mothers who had not. Mothers and fathers of PHAs (persons with HIV/AIDS) who died reported lower levels of overall happiness compared to 3 years previously (before the time of the death of their child) and compared to parents from households that did not experience an adult child's death. Many parents of children with AIDS experienced anxiety, insomnia, fatigue, muscle strain, and head and stomach aches during the time they cared for their ill children. Many older people suffered adverse health outcomes related to living with and caring for their children with AIDS. Recommendations indicate a variety of programs that might help such older parents.

Identification of novel mutations in the NPC1 gene in German patients with Niemann-Pick C disease.

Niemann-Pick disease type C (NPC) is an inherited neuro-degenerative disorder associated with intracellular cholesterol trafficking defects. Mutations in two distinct genes, NPC1 and HE1, have recently been shown to cause this disease. We have analysed the NPC1 gene in five German patients with NPC from four unrelated families. We identified a total of five novel mutations in the coding region of the NPC1 gene (G231V, D874V, 1642M, 11094T and R116stop). All affected individuals displayed compound heterozygosity. The mutated alleles were transmitted by the nonaffected parents with the exception of one patient, in whom a de novo mutation (G231V) had occurred. Interestingly, the G231V/P237S NPC1 genotype in this individual is associated with an early-onset form of NPC. In contrast, we found that the D874V/D948N genotype, observed in another NPC patient, is characterized by a late onset of clinical symptoms that presents with a pronounced white-matter disease. Our results will contribute to defining the association between the clinical phenotypes and the genetic abnormalities in Niemann-Pick C disease.

Genes and Microbes Linked at Last

Genes and Microbes Linked at Last

PMP22 Mutations In DÉJÈRine‐Sottas Disease: A Mutational “Hot Spot” On Codon 72

Increased dosage of the gene encoding the peripheral myelin protein PMP22 is the most common molecular mechanism underlying the demyelinating form of Charcot‐Marie‐Tooth disease (CMT1A). It results from the duplication of a 1.5‐Mb tract on chr. 17p11.2 which encompasses the PMP22 gene. Mutations in this gene can also cause CMT1A and are often associated with more severe phenotypes such as Déjèrine‐Sottas disease (DSD) and congenital hypomyelinating neuropathy (CHN). We have analyzed the PMP22 gene in 20 unrelated patients affected with a severe form of demyelinating motor and sensory neuropathy (severe CMT1 or DSD). All the patients had been found negative for the common CMT1A duplication and for mutations in the myelin protein P0 gene (MPZ). Direct sequence analysis of PMP22 uncovered the presence of missense mutations in 3 patients diagnosed as having DSD. In each case, the mutation was heterozygous and was not carried by any of the nonaffected parents, thus indicating that it was a de novo dominant mutation. Patient #1, a 3‐y‐old boy, carried a C‐to‐T transition in PMP22 exon 4 which would result in the amino acid substitution of Leu‐80 with Pro in the 2nd transmembrane domain of the protein. This mutation had been previously observed in another DSD patient (Tyson, 1997). Patient #2, a 3‐y‐old girl, and patient #3 carried the same mutation, the 215C‐to‐T transition in exon 4. Interestingly, patient #3 was a 35‐y‐old man born of consanguineous healthy parents. The disease had started during the first years of life and the patient had become wheelchair‐bound at the age of 28 y. The 215C‐to‐T mutation eliminates a TaqI restriction site and results in the substitution of Ser‐72 (TCG) with Leu (TTG) in the 2nd transmembrane domain of PMP22. Approx. 40 different PMP22 mutations are currently listed in the European CMT Consortium Database. In the majority of cases, the mutations have been identified in single or very few patients, with the only exception of the Ser72Leu substitution. Including the two unrelated patients reported here, this mutation has been thus far described in a total of 7 patients. The mutation, which occurs within a CpG dinucleotide, exhibits phenotypic heterogeneity and has been observed in both DSD (6) and CHN (1) cases. In conclusion, PMP22 mutations are rare causes of genetic neuropathies. Given the limited number of such mutations, the recurrence of substitutions at codon 72 would indicate that this may represent a mutational “hot spot”. We therefore suggest that sequence analysis of PMP22 exon 4 should routinely precede analysis of the remaining exons and intron/exon boundaries.

Familial history, age and smoking are important risk factors for disc degeneration disease in Arabic pedigrees.

The present study used computed tomography imaging to evaluate the extent and pattern of the intergenerational transmission of spinal disc degeneration disease (DDD) in complex pedigrees. Contribution of a number of the potential covariates was also studied using univariate and multivariate logistic regression analysis, as well as two types of complex segregation analysis models. Among 161 individuals studied, DDD was diagnosed in 60 individuals. The number of protruded discs varied from 1 to 4, mostly in lumbar or lumbosacral regions. The average age at onset of the disease was similar for both women (36.0 years) and men (34.8 years). The proportion of the individuals affected by the DDD status of their parents ranged from 10% in families of two healthy parents to 55.5% of two affected parents (p < 0.01). The results of the logistic regression analyses and complex segregation analysis were qualitatively the same: DDD status of parents, age and smoking were the main risk factors for disc herniation in the Arabic families we examined. All analyses showed a predominating role of the family history as a risk factor for DDD in offsprings. It showed, for example, four times higher risk at age 50 for individuals with two affected parents vs. those who have two non-affected parents. However, the results of models-fitting genetic analysis, did not confirm a monogenic Mendelian pattern of inheritance.

Seizure risk in offspring of individuals with a history of febrile convulsions.

One-hundred and seventy-nine offspring of 120 probands with a history of febrile convulsions (FC) were studied to determine the risk of seizures and possible factors influencing this risk. The conditions for this study were especially good since all of the probands had undergone clinical and EEG examinations as well as an assessment of family history of seizures during childhood. Hence, for the first time the seizure status of the probands' parents could be included in the calculation of risk in offspring. In sibs the risk was highest if the mother of the proband had experienced seizures (20% vs 9% in offspring of probands with nonaffected parents). Similarly, offspring of probands with affected mothers had a much higher risk (27%) than offspring of probands with affected fathers (7%). Our findings point to a maternal preponderance in the transmission of FC liability. No relationship was found between the presence of EEG traits of a genetic seizure liability (theta rhythms, spikes and waves, photoparoxysmal response, focal sharp waves) in probands during childhood and the seizure risk in their offspring. The present data provide no basis for forming an hypothesis regarding the possible mode of inheritance of FC. This is not surprising since FC as already shown in the EEG-are not a homogeneous disorder, but are caused by a variety of genetic factors occurring in variable constellations. Possibly, in a subgroup of probands with seizure affected mothers the susceptibility to FC follows a multifactorial polygenic mode of inheritance. The seizure incidence in offspring of individuals with a history of FC was 10% (only FC in 64% of the affected offspring). Offspring of females with affected parents were at an increased risk. Pathological childhood EEG findings of the probands were not related to an increased risk in offspring.

Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is generally the consequence of an interstitial microdeletion at 7q11.23, which includes the elastin gene, thus causing hemizygosity at the elastin gene locus. The origin of the deletion has been reported by many authors to be maternal in approximately 60% and paternal in 40% of cases. Segregation analysis of grandparental markers flanking the microdeletion region in WBS patients and their parents indicated that in the majority of cases a recombination between grandmaternal and grandpaternal chromosomes 7 at the site of the deletion had occurred during meiosis in the parent from whom the deleted chromosome stemmed. Thus, the majority of deletions were considered a consequence of unequal crossing-over between homologous chromosomes 7 (interchromosomal rearrangement) while in the remaining cases an intrachromosomal recombination (between the chromatids of one chromosome 7) may have occurred. These results suggest that the majority of interstitial deletions of the elastin gene region occur during meiosis, due to unbalanced recombination while a minority could occur before or during meiosis probably due to intrachromosomal rearrangements. The recurrence risk of the interchromosomal rearrangements for sibs of a proband with non-affected parents must be negligible, which fits well with the observation of sporadic occurrence of almost all cases of WBS.

Unexpected sex-ratios in families of language/ learning-impaired children: Evidence from genetic familial studies

Based on the increased incidence of boys to girls affected with developmental language impairments (LI), sex-linked models of genetic transmission were investigated. Family history data was collected on all first-degree relatives of a large, well-defined population of (LI) children and matched normal controls. Results demonstrated significant family aggregation in all first-degree relatives of LIs as compared to controls. Further analyses demonstrated that the expected higher male to female sex-ratio in LI children only occurred significantly in families with an affected parent. Affected mothers, but not fathers, demonstrated a significant sex-ratio difference among probands as well as increased frequency of other affected offspring. However, results failed to support sex-linkage hypotheses in that male and female probands had equal propensity to have an affected mother or father and did not differ in rate or sex of affected siblings. An unexpected finding was that the siblings of LI children also demonstrated a significantly aberrant sex-ratio. LI children had 65 brothers, but only 35 sisters (ratio 1.9:1). Analyses demonstrated that, whereas non-affected parents and affected fathers had the expected equal number of male and female offspring, affected mothers had three times as many male as female offspring and eight times as many affected males as females (excluding probands). Genetic and hormonal influences that might affect sex-ratio, brain development and neurodevelopmental disorders will be discussed.

Co‐segregation of HLA and rheumatoid arthritis in multicase families

Inheritance of parental HLA haplotypes was examined in the offspring of 95 multicase rheumatoid arthritis (RA) families. Overall, in these families there was no evidence of preferential transmission of one parental haplotype, although this might have been expected given the loading of these families with RA cases. However, there was a difference in inheritance when the affected and non-affected offspring were compared. A co-segregation analysis showed that the inheritance of parental HLA haplotypes was different between the affected and the unaffected offspring. Unlike a previous report, no difference was demonstrated in this study between the offspring of affected and non-affected parents. Similarly, the affected offspring of HLA DR4 heterozygote parents were more likely to inherit HLA DR4 than the non-affected offspring. It is concluded first that linkage studies of RA using the affected sib-pair method are not invalidated, which would have been the case in the presence of preferential transmission of HLA to all offspring. Secondly, HLA and specifically HLA-DR4 does co-segregate with RA, and, finally, parental RA status, independent of DR4, has little influence in explaining the genetic susceptibility to RA.

Genetic heterogeneity of Alport syndrome

Forty-one families have been studied with stringent diagnostic criteria of Alport syndrome: proven renal disease with hematuria affecting at least two relatives, neural hearing loss in at least one affected individual, and evolution to renal failure in at least one affected individual. The proportion of affected offsprings of affected females does not significantly differ from the ratio expected for a dominant trait. The descendance of affected males shows a lack of affected males. In four families, with parental consanguinity and nonaffected parents, the findings agree with an autosomal recessive inheritance. Study of quantitative traits such as death or renal death among brothers, uncle-nephew pairs and whole families shows evident intra-familial resemblances. We conclude that Alport syndrome seems to be a heterogeneous state composed of a number of genetically distinct syndromes, with an autosomal dominant, an X-linked dominant, and an autosomal recessive form.

Schizoaffective disorders: Results of a genetic investigation, I

1004 first degree relatives of 150 schizoaffective patients (41 males, 109 females) were studied and a total morbidity risk of 29.6% of schizoaffective spectrum disorders were found. The relatives show an increased morbidity risk for schizophrenia (5.26%) and affective disorder (6.55%) with a high incidence of catatonia and unipolar depression; schizoaffective secondary cases were only found in 3%. There is no significant difference in morbidity between parents, siblings and children. The morbidity risk of neuroses is 5.3%, for personality disorders 7.2% and for suicides without spectrum diagnosis 1.8%. Off-spring of affected parents show a morbidity risk twice as high as that of off-spring of non-affected parents. The findings do not support the present concept of the ICD (International Classification of Disorders) of WHO, which subsumes schizoaffective disorders under the major rubric of schizophrenia. From a genetic viewpoint schizoaffective disorder takes an intermediate position between schizophrenia and affective disorders. None of the present hypotheses of the mode of inheritance is supported by the findings.

The Laurence-Moon-Biedl Syndrome in a Singhalese Family

The first published occurrence of the Laurence-Moon-Biedl Syndrome in a Singhalese family is reported. Three members of a family of six with first cousin non-affected parents are described along with studies to indicate that the hypogonadism in this family can be ascribed to hypogonadotrophism. The high incidence of congenital heart disease and genito-urinary abnormalities noted by other is confirmed.

Ureteral Reflux as Genetic Trait

In a study of pedigrees of ten families, an increased frequency of ureteral reflux was found. Some members with ureteral reflux do not show any other symptoms. The distribution of affected individuals in sibships suggests a dominant gene, but the fact that affected offspring are frequently found in families of two nonaffected parents contradicts this assumption. The involvement of a dominant gene with incomplete expression is tentatively proposed.