Family Genetic Studies Research Articles

Late-onset hereditary axonal neuropathies

Hereditary motor-sensory neuropathy or the Charcot-Marie-Tooth syndrome is known to represent considerable genetic heterogeneity. Onset is usually in childhood, adolescence, or young adulthood. The objective of this study was to define late-onset forms of the disorder. A clinical and genetic study of families with uniformly late onset of peripheral neuropathy was performed in a university neurogenetics setting. Six families were identified with consistently late onset of a primarily axonal neuropathy. Median age at symptom onset was 57 years (range 35-85 years) of a mixed motor and sensory neuropathy with electrophysiologic characteristics of an axonal rather than demyelinating condition. There was a possible association with deafness. Two families showed autosomal dominant inheritance whereas four families had only one affected generation with an excess of males. An extensive mutation screen of nine genes known to cause Charcot-Marie-Tooth was negative. There are late-onset forms of hereditary axonal neuropathies. The genetic causes remain unknown and genetic heterogeneity within this entity is likely.

Hereditary Spastic Paraplegia With Mental Impairment and Thin Corpus Callosum in Tunisia

To perform a clinical and genetic study of Tunisian families with autosomal recessive (AR) hereditary spastic paraplegia with thin corpus callosum (HSP-TCC). Linkage studies and mutation screening. Reference Center for Neurogenetics in South and Center Tunisia. Seventy-three subjects from 33 "apparently" unrelated Tunisian families with AR HSP. Families with AR HSP-TCC were subsequently tested for linkage to the corresponding loci using microsatellite markers from the candidate intervals, followed by direct sequencing of the KIAA1840 gene in families linked to SPG11. We identified 8 Tunisian families (8 of 33 [24%]), including 19 affected patients, fulfilling the clinical criteria for HSP-TCC. In 7 families, linkage to either SPG11 (62.5%) or SPG15 (25%) was suggested by haplotype reconstruction and positive logarithm of odds score values for microsatellite markers. The identification of 2 recurrent mutations (R2034X and M245VfsX) in the SPG11 gene in 5 families validated the linkage results. The neurological and radiological findings in SPG11 and SPG15 patients were relatively similar. The remaining family, characterized by an earlier age at onset and the presence of cataracts, was excluded for linkage to the 6 known loci, suggesting further genetic heterogeneity. Autosomal recessive HSP-TCC is a frequent subtype of complicated HSP in Tunisia and is clinically and genetically heterogeneous. SPG11 and SPG15 are the major loci for this entity, but at least another genetic form with unique clinical features exists.

Gene-environment interaction in posttraumatic stress disorder

The purpose of this article is to encourage research investigating the role of measured gene-environment interaction (G x E) in the etiology of posttraumatic stress disorder (PTSD). PTSD is uniquely suited to the study of G x E as the diagnosis requires exposure to a potentially-traumatic life event. PTSD is also moderately heritable; however, the role of genetic factors in PTSD etiology has been largely neglected both by trauma researchers and psychiatric geneticists. First, we summarize evidence for genetic influences on PTSD from family, twin, and molecular genetic studies. Second, we discuss the key challenges in G x E studies of PTSD and offer practical strategies for addressing these challenges and for discovering replicable G x E for PTSD. Finally, we propose some promising new directions for PTSD G x E research. We suggest that G x E research in PTSD is essential to understanding vulnerability and resilience following exposure to a traumatic event.

DeFries–Fulker and Pearson–Aitken Model-fitting Analyses of Reading Performance Data from Selected and Unselected Twin Pairs

Although a comparison of concordance rates for deviant scores in identical and fraternal twin pairs can provide prima facie evidence for a genetic etiology, information is not fully utilized when continuous measures are analyzed in a dichotomous manner. Thus, DeFries and Fulker (Behav Genet 15:467-473, 1985; Acta Genet Med Gemellol, 37:205-216, 1988) developed a regression-based methodology (DF analysis) to assess genetic etiology in both selected and unselected twin samples. While the DF analysis is a very versatile and relatively powerful statistical approach, it is not easily extended to the multivariate case. In contrast, structural equation models may be readily extended to analyze multivariate data sets (Neale and Cardon, Methodology for genetic studies of twins and families, 1992). However, such methodologies may yield biased estimates of additive genetic, shared environmental, and non-shared environmental influences when multivariate models are fitted to selected twin data. Therefore, the Pearson-Aitken (PA) selection formula (Aitken, Proc Edinburgh Math Soc B, 4:106-110, 1934) was used to analyze reading performance data from twins with reading difficulties (selected sample) and a population of normally-achieving twin pairs (control sample). As a comparison, DF models were also fitted to these same data sets. In general, resulting estimates of additive genetic, shared environmental, and non-shared environmental influences were similar when the DF and PA models were fitted to the data. However, the PA selection formula may be more readily generalized to the multivariate case.

α-Synuclein gene duplications in sporadic Parkinson disease

Heritability of Parkinson disease (PD) has long been disputed since patients seldom had a positive family history of the disease. Nevertheless, during the last decade genetic linkage studies in rare Mendelian PD families identified six genes in which mutations were associated with PD.1 In fact, most current knowledge of molecular pathogenesis of PD results from functional studies of the proteins encoded by these PD genes. At present, our improved insight into genetic risk for PD contributes to a more accurate diagnosis and provides rationales for new therapeutic approaches based on powerful model systems of mutated PD genes. The first PD gene identified was the α-synuclein gene ( SNCA ) in which a pathogenic missense mutation—p.Ala53Thr (c.157G>A)—segregated with PD in the autosomal dominant Contursi kindred.2 Two more missense mutations were identified in a German (c.88G>C; p.Ala30Pro) and a Spanish (c.136G>A; p.Glu46Lys) family.1 These mutations supported a direct link between α-synuclein dysfunction and the appearance of Lewy bodies of this protein in PD brains, and are expected to cause PD via a toxic gain-of-function of mutant SNCA protein. Later, a major role for wild type SNCA in PD pathogenesis …

Expression studies of osteoglycin/mimecan ( OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

Genes involved in the hearing process have been identified through both positional cloning efforts following genetic linkage studies of families with heritable deafness and by candidate gene approaches based on known functional properties or inner ear expression. The latter method of gene discovery may employ a tissue- or organ-specific approach. Through characterization of a human fetal cochlear cDNA library, we have identified transcripts that are preferentially and/or highly expressed in the cochlea. High expression in the cochlea may be suggestive of a fundamental role for a transcript in the auditory system. Herein we report the identification and characterization of a transcript from the cochlear cDNA library with abundant cochlear expression and unknown function that was subsequently determined to represent osteoglycin ( OGN). Ogn-deficient mice, when analyzed by auditory brainstem response and distortion product otoacoustic emissions, have normal hearing thresholds.

El espectro de la fiebre mediterránea familiar

Familial mediterranean fever (FMF) is a disease whose importance in recent years is reappearing thanks to the advances in molecular genetics. The diagnosis is established by symptoms, presence of inflammatory episodes of fever and serositis, family background and genetic study. Identification of the most prevalent mutations of the MEFV gene may confirm atypical or incomplete forms of FMS that are difficult to recognize based on the classical major and minor criteria. Knowledge of this more extensive clinical spectrum makes it possible to have a new diagnostic and therapeutic perspective based on the treatment of colchicine and secondary prevention of AA amyloidosis.

A novel mutation of the β‐globin gene promoter (−102 C>A) and pitfalls in family screening

We describe a family with beta-thalassemia in which several pitfalls of genetic diagnoses were present. These include coherent family phenotypes with discrepancies in molecular findings because of nonpaternity, and a false beta-globin gene homozygous genotype due to a large deletion in the second locus. These findings underline the difficulties of family genetic studies and the need for tight relationship between professionals involved in laboratory studies and those in-charge of the clinical follow-up and genetic counselling. In this family, we also report a new silent beta-thalassemia mutation, -102 (C>A), in the distal CACCC box of the beta-globin gene promoter.

Family-genetic study of executive functioning in attention-deficit/hyperactivity disorder: Evidence for an endophenotype?

This study examined familiality of attentional control and mental flexibility in multiplex attention-deficit/hyperactivity disorder (ADHD) families. The authors hypothesized that siblings of ADHD probands, although not behaviorally expressing ADHD, have deficits in these executive functions and that the performance of probands, unaffected siblings, and control participants are on a continuum. Participants (aged 6 to 17) were 25 ADHD probands with a family history of ADHD, their 25 unaffected siblings, and 48 control participants. The unaffected siblings did not differ from the ADHD probands on attentional control or on some measures of mental flexibility. Linear changes in performance across the groups reflected an intermediate position of the unaffected siblings between the probands and control participants. These results suggest that these executive functions may be suitable endophenotypes of ADHD.

Genetics of posttraumatic stress disorder: Review and recommendations for future studies

Posttraumatic stress disorder (PTSD) is common and debilitating. Posttraumatic stress disorder is moderately heritable; however, the role of genetic factors in PTSD etiology has been largely neglected by trauma researchers. The goal of this study is to motivate trauma researchers to reflect on the role genetic variation may play in vulnerability and resilience following trauma exposure. Evidence from family, twin, and molecular genetic studies for genetic influences on PTSD is reviewed. Recommendations for future studies are presented with emphasis on study design and assessment issues particular to the field of trauma and PTSD. Clinical implications of PTSD genetic studies are discussed.

Vascular anomalies

Vascular anomalies

Risperidone-Induced Priapism in a 12-Year-Old Boy with Schizophrenia

To examine whether adverse perinatal experiences of children are associated with obsessive compulsive disorder (OCD) in youth.Subjects were 130 children and adolescents with OCD recruited from a family genetic study of pediatric OCD and 49 matched controls from a contemporaneous family case-control study of attention-deficit/hyperactivity disorder (ADHD). Subjects were comprehensively assessed in multiple domains of function. A systematic history of pregnancy, delivery, and infancy complications was obtained.Compared to normal controls, children with OCD had mothers with significantly higher rates of illness during pregnancy requiring medical care (chi(2) +/- 8.61, p +/- 0.003) and more birth difficulties (induced labor, forceps delivery, nuchal cord, or prolonged labor) (chi(2) +/- 7.51, p +/- 0.006). Among the OCD-affected children, we found several significant associations between adverse perinatal experiences and earlier age at onset, increased OCD severity, and increased risk for comorbid ADHD, chronic tic disorder, anxiety disorder, and major depressive disorder.Although exploratory, our analyses found that children with OCD had higher rates of several adverse perinatal experiences compared with controls. Among OCD-affected children, comorbid psychopathology was predicted by specific perinatal risk factors. Prospective studies of perinatal adverse events that minimize potential recall bias and type I errors are needed.

Hipobetalipoproteinemia familiar secundaria a mutación en el gen de la apolipoproteína B

Familial hypobetalipoproteinemia (FHB) is a rare genetically heterogeneous disorder provoking abnormally low serum levels of apoprotein (apo) B, total cholesterol, and low-density lipoprotein (LDL-C). Patients carrying heterozygous mutations in the APOB (2p24) gene are usually asymptomatic, but homozygous mutations cause clinical disturbances as a result of intestinal fat malabsorption and fat-soluble vitamin deficiency. We present an asymptomatic boy, aged 8 years and 7 months, with low serum levels of apo-B, total cholesterol, triglyceride, LDL-C and very low-density lipoprotein (VLDL-C), as well as vitamin E deficiency. Three asymptomatic relatives also exhibited low apo-B, total cholesterol and LDL-C levels. The APOB (2p24) gene was fully sequenced, demonstrating a heterozygous mutation in exon 26 (G --> T) in all four members of this family. Familial genetic studies in FHB could be useful in the early detection and treatment of homozygous carriers.

Gender differences in severity of writing and reading disabilities

Gender differences in mean level of reading and writing skills were examined in 122 children (80 boys and 42 girls) and 200 adults (115 fathers and 85 mothers) who showed behavioral markers of dyslexia in a family genetics study. Gender differences were found in writing and replicated prior results for typically developing children: Boys and men were more impaired in handwriting and composing than were girls and women, but men, who were more impaired in those writing skills, were also more impaired in spelling than women. Men were more impaired than women in accuracy and rate of reading passages orally, but boys were not more impaired than girls on any of the reading measures. Males were consistently more impaired than females in orthographic skills, which may be the source of gender differences in writing, but not motor skills. Population-based studies that report gender differences in reading in children with dyslexia may be confounding reading and writing disorders—the latter being the true source of gender differences in both children and adults with dyslexia.

Targeting the dopamine system in the treatment of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable condition that affects a significant number of children and adults worldwide. During the past 30 years, the diagnosis and treatment of ADHD has relied on clinical assessment and empirical experience with stimulant medications. More recently, advances in family genetic studies, molecular genetic studies, preclinical research, radiographic imaging techniques and neuropsychological evaluation have significantly enhanced our understanding of the neurobiology of ADHD. This review highlights the current central role of dopamine in the pathophysiology and treatment of ADHD and implications for future advances in diagnosis and treatment.

Size Matters: The Unexpected Challenge of Detecting Linkage in Large Cohorts

Size Matters: The Unexpected Challenge of Detecting Linkage in Large Cohorts

Late-onset central hypoventilation syndrome: a family genetic study

Congenital central hypoventilation syndrome is a rare disorder characterised by chronic alveolar hypoventilation, which becomes more pronounced during sleep and may be associated with neurocristopathies, such as Hirchsprung's disease. A mutation in the PHOX2B gene has recently been identified. In a family of both parents and five offspring, detailed clinical assessment, pulmonary function testing, overnight sleep studies and ventilatory responsiveness to progressive hypercapnia (V'(R,CO(2))) were performed, in addition to analysis of known genetic loci for this condition. The father and four of the offspring demonstrated features of central hypoventilation with nonapnoeic oxygen desaturation during sleep and diminished V'(R,CO(2)), despite normal pulmonary function. The lowest sleep saturation was median (range) 79% (67-83%) and V'(R,CO(2)) was 2.1 (0.03-4.3) L x min(-1) x kPa(-1). The normal values for the authors' centre (St Vincent's University Hospital, Dublin, Ireland) are 15-40 L x min(-1) x kPa(-1). An in-frame five amino acid polyalanine expansion of the PHOX2B gene was found in all affected subjects, while the mother and fifth child, who did not have features of central hypoventilation, had a normal PHOX2B gene. Magnetic resonance imaging of the brainstem in one severely affected child was normal. The present study of a unique family confirms that transmission of late-onset congenital central hypoventilation syndrome is autosomal dominant in nature.

Writing problems in developmental dyslexia: Under-recognized and under-treated

The International Dyslexia Association defines dyslexia as unexpected problems of neurobiological origin in accuracy and rate of oral reading of single real words, single pseudowords, or text or of written spelling. However, prior research has focused more on the reading than the spelling problems of students with dyslexia. A test battery was administered to 122 children who met the inclusion criteria for dyslexia and qualified their families for participation in a family genetics study that has been ongoing for over a decade. Their parents completed the same test battery. Although a past structural equation modeling study of typically developing children identified a significant path from handwriting to composition quality, the current structural equation modeling study identified a significant path from spelling to composition for children and their parents with dyslexia. Grapho-motor planning did not contribute uniquely to their composition, showing that writing is not just a motor skill. Students with dyslexia do have a problem in automatic letter writing and naming, which was related to impaired inhibition and verbal fluency and may explain their spelling problems. Results are discussed in reference to the importance of providing explicit instruction in the phonological, orthographic, and morphological processes of spelling and in composition to students with dyslexia and not only offering accommodation for their writing problems.

Correlations between cephalometric and facial photographic measurements of craniofacial form

The purpose of this study was to compare craniofacial measurements from cephalometric radiographs with analogous measurements from standardized facial photographs. The sample consisted of 326 subjects (168 white, 158 black) enrolled in a genetic epidemiological family study of sleep behavior. Traditional lateral cephalograms and standardized facial photographs were taken of each subject. Three angular, 3 linear, total face height, and lower face height cephalometric measurements were compared with 4 angular and 4 linear measurements from standardized photographs. Descriptive statistics for all measurements in the entire sample and for the racial subgroups were computed. Pearson product moment correlation coefficients were computed between analogous measurements, and intraclass correlation coefficients were calculated from repeated measurements on the photographs. The reliability of the photographic technique was excellent, with all measurements having intraclass correlation coefficients above 0.90. However, the correlations between analogous photographic and cephalometric measurements were lower and varied between 0.356 and 0.643. The highest correlations were observed for lower facial height and mandibular length, 0.643 and 0.562, respectively. In the black group, the correlations between cephalometric and photographic measurements of mandibular length and lower facial height were 0.676 and 0.690, respectively. Both were higher than those for white subjects, 0.399 and 0.577, respectively. Both linear and angular measurements useful for characterizing facial morphology can be reliably measured from facial photographs. However, only moderate correlations with analogous cephalometric measures were found. Therefore, standardized photographs and cephalograms most likely measure different aspects of facial morphology and cannot be used interchangeably. Cephalometrics remains the method of choice for clinical patient care, whereas photographs might be better for large-scale epidemiological studies, especially if there is a need for a low-cost, noninvasive method that be used in diverse clinical and field settings.

The Genetics of Gambling and Behavioral Addictions

Behavioral addictions are considered as the repetitive occurrence of impulsive behaviors without consideration of their potential negative consequences. These addictions represent an increasing cost to society and are an important new field of research in psychiatric genetics. There has been a growing body of evidence on the familial aggregation and genetic influences on the development of behavioral addictions and mainly on pathological gambling. The aim of this article is to critically review findings of family and molecular genetic studies on behavioral addictions, focusing on pathological gambling and commenting on other disorders where appropriate. This review provides a comprehensive approach to genetic studies on behavioral addiction and points out the necessity of expanding the genetic research in this field. Future directions for genetic studies in this field are also discussed.