Sulcus vocalis: evidence for autosomal dominant inheritance

We found evidence of autosomal dominant hereditary transmission of sulcus vocalis. Four dysphonic patients from three generations of the same family were submitted to videolaryngoscopic examination (three patients) and to direct laryngoscopy (one patient) to diagnose the hoarseness. Sulcus vocalis was diagnosed in all four patients. The finding of four affected individuals in three generations, with vertical transmission affecting man and women, is more consistent with autosomal dominant inheritance pattern; it is an etiological model that we propose for the sulcus vocalis in this pedigree.     

病理性近视的家系研究

为了探讨我国病理性近视的遗传模式,对90个病理性近视大家系进行了分离分析。简单分离分析采用先验法和SEGRAN-B软件,进行拟合优度卡方检验,比较实际分离比与理论分离比的符合程度;复合分离分析运用SAGE-REGD软件进行孟德尔遗传模型(主基因、显性、隐性、共显性)和非孟德尔遗传模型(非传递、环境、一般)的拟合。结果显示,婚配类型为A*N的家系符合常染色体显性遗传,散发概率为13．8％,婚配类型为N*N的家系符合常染色体隐性遗传,散发概率为16．3％,但常染色体显性遗传不能除外,复合分离分析接受孟德尔遗传的显性、隐性、共显性和主基因模型,共显性模型的可能性最大,基因频率为0．21442999。因此,我国病理性近视存在常染色体显性和隐性遗传模式,并有一定比例的散发病例,具有遗传异质性。     

Retinitis pigmentosa: distribution of inheritance patterns in a VA blind rehabilitation center population

Objectives: This purpose of this study was to characterize retinitis pigmentosa (RP) patients at the Southeastern Blind Rehabilitation Center (SBRC) by inheritance pattern, and compare the results with similar studies. Study Design: Records of all RP patients who were in the blind rehabilitation program at the SBRC between 1989 and 1993 were reviewed (n=50). Patients were included in the study who could be personally contacted and whose records were complete (n=43). Pedigrees were obtained through review of records and patient interviews. Results: The analysis showed 24 patients (55.8%) were simplex (no family history of RP), 8 patients (18.6%) were autosomal dominant, 4 patients (9.3%) were probable autosomal dominant, 4 patients (9.3%) were autosomal recessive, 2 patients (4.7%) were probable autosomal recessive and 1 patient (2.3%) was X-linked recessive. Conclusions: Unique trends were apparent in the distribution of inheritance patterns. Clinicians should be aware of the large number of simplex patients found in this and the majority of similar studies.     

Genomewide linkage scan for split-hand/foot malformation with long-bone deficiency in a large Arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1

Split-hand/foot malformation with long-bone deficiency (SHFLD) is a rare, severe limb deformity characterized by tibia aplasia with or without split-hand/split-foot deformity. Identification of genetic susceptibility loci for SHFLD has been unsuccessful because of its rare incidence, variable phenotypic expression and associated anomalies, and uncertain inheritance pattern. SHFLD is usually inherited as an autosomal dominant trait with reduced penetrance, although recessive inheritance has also been postulated. We conducted a genomewide linkage analysis, using a 10K SNP array in a large consanguineous family (UR078) from the United Arab Emirates (UAE) who had disease transmission consistent with an autosomal dominant inheritance pattern. The study identified two novel SHFLD susceptibility loci at 1q42.2-q43 (nonparametric linkage [NPL] 9.8, P=.000065) and 6q14.1 (NPL 7.12, P=.000897). These results were also supported by multipoint parametric linkage analysis. Maximum multipoint LOD scores of 3.20 and 3.78 were detected for genomic locations 1q42.2-43 and 6q14.1, respectively, with the use of an autosomal dominant mode of inheritance with reduced penetrance. Haplotype analysis with informative crossovers enabled mapping of the SHFLD loci to a region of approximately 18.38 cM (8.4 Mb) between single-nucleotide polymorphisms rs1124110 and rs535043 on 1q42.2-q43 and to a region of approximately 1.96 cM (4.1 Mb) between rs623155 and rs1547251 on 6q14.1. The study identified two novel loci for the SHFLD phenotype in this UAE family.     

Cutaneous malignant melanoma and familial dysplastic nevi: evidence for autosomal dominance and pleiotropy.

Segregation of familial cutaneous melanoma has been shown to be compatible with autosomal dominant transmission with incomplete penetrance. However, the combined phenotype of melanoma and a known melanoma-precursor lesion, the dysplastic nevus (DN), has not previously been found to fit a Mendelian model of inheritance using complex segregation analysis. Employing a life-table and disease-free survival analysis approach, we estimated the lifetime incidence of melanoma in the sibs and offspring of DN-affected individuals to be 46%, consistent with a highly penetrant, autosomal dominant mode of inheritance. To further elucidate the relationship between the two traits, we conducted a linkage analysis between the melanoma locus and a hypothetical DN locus, and obtained a maximum lod score of 3.857 at theta = .08. Furthermore, all families giving evidence for linkage were in the coupling phase and the maximum likelihood estimate of theta was not significantly different from 0 (P = .1). This provides evidence that the DN and melanoma traits may represent pleiotropic effects of a single, highly penetrant gene behaving in an autosomal dominant manner.     

Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.

Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown etiology, characterized by impaired myocardial contractility and ventricular dilatation. The disorder is an important cause of morbidity and mortality and represents the chief indication for heart transplantation. Familial transmission is often recognized (familial dilated cardiomyopathy, or FDC), mostly with autosomal dominant inheritance. In order to understand the molecular genetic basis of the disease, a large six-generation kindred with autosomal dominant FDC was studied for linkage analysis. A genome-wide search was undertaken after a large series of candidate genes were excluded and was then extended to two other families with autosomal dominant pattern of transmission and identical clinical features. Coinheritance of the disease gene was excluded for > 95% of the genome, after 251 polymorphic markers were analyzed. Linkage was found for chromosome 9q13-q22, with a maximum multipoint lod score of 4.2. There was no evidence of heterogeneity. The FDC locus was placed in the interval between loci D9S153 and D9S152. Several candidate genes for causing dilated cardiomyopathy map in this region.     

Genetic counseling in craniostenosis. Results of a prospective study performed with a group of studies on craniofacial malformations

Result of a family study based on 584 patients with craniostenosis brings some answers useful for genetic counselling. For 98 patients (15%) a syndrome is associated. Third part of them has Apert syndrome, an other third part has Crouzon syndrome, and for the last third more exceptional acrocephalosyndactyly syndrome (Saethre-Chotzen, Pfeiffer) or others atypical associations, sometimes not yet described, but with an autosomal dominant inheritance. Non syndromic craniostenosis involves differently according to the type of join, but the localization is the same if recurrence will be happen. Coronal craniostenosis seems to be a dominant autosomal character, when scaphocephaly is more often sporadic; for both, an autosomal dominant inheritance is not excluded for some pedigrees. If the recurrence risk exist in some cases, it is generally well accepted by parents on account of the good neurosurgeon prognosis.     

Molecular pathogenesis of neonatal hypothyroidism

In patients with congenital hypothyroidism (CH), the autosomal recessive inheritance of mutations of thyroid peroxidase, thyroglobulin and the NIS and pendrin genes encoding for sodium iodide transporters has been identified. CH due to thyroid dysgenesis was considered to be a sporadic disease, but recently, inheritable defects of thyroid development have been described. The autosomal recessive inheritance of mutations of the thyroid-stimulating hormone receptor gene was recognized in patients with CH and thyroid hypoplasia, while autosomal dominant mutations of the Pax-8 gene were described in patients with thyroid dysgenesis. In addition, analysis of mutations of the beta-thyrotropin gene has resulted in a new understanding of the pathogenesis of central CH. Molecular genetic studies in patients with CH detected by newborn screening will provide the information necessary for genetic counselling and may help to explain the less favourable outcome present in 5-10% of the patients.     

Immunofluorescence of mineralocorticoid receptors in peripheral lymphocytes: Presence of receptor-like activity in patients with the autosomal dominant form of pseudohypoaldosteronism, and its absence in the recessive form

Pseudohypoaldosteronism is a syndrome characterized by salt wasting and a failure to thrive due to the resistance towards the action of aldosterone. Aldosterone levels and plasma renin activity are extremely elevated and aldosterone binding sites in peripheral mononuclear leukocytes have regularly shown to be reduced or absent. Sporadic as well as familial cases have been identified and an autosomal dominant as well as an autosomal recessive mode of inheritance has been described. A defect in the aldosterone receptor has been postulated, however, molecular genetic analysis in selected patients has not revealed a mutation in the sequence of the coding region of the cDNA of the mineralocorticoid receptor gene. In the present study we have used a fluorescence-labeled antibody to detect possible receptor expression in monocytes from patients with various clinical forms of pseudohypoaldosteronism. Patients with the sporadic as well as with the autosomal dominant form were clearly immunopositive despite being negative in terms of aldosterone receptor binding. In contrast in two patients with the autosomal recessive form there was no detectable receptor protein, consistent with the results obtained in the aldosterone binding studies. These results suggest that the pathogenesis of pseudohypoaldosteronism is heterogeneous not only regarding the mode of inheritance but also in terms of receptor binding. Thus, in a subgroup of patients the inability of the receptor to bind ligand may be due to a defect involving other, probably cellular factors rather than a deficiency or a defect in the mineralocorticoid receptor system itself.     

Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele.

Erythropoietic protoporphyria (EPP) is a monogenic inherited disorder of the heme biosynthetic pathway due to ferrochelatase (FC) deficiency. EPP is generally considered to be transmitted as an autosomal dominant disease with incomplete penetrance, although autosomal recessive inheritance has been documented at the enzymatic and molecular level in some families. In the dominant form of EPP, statistical analysis of FC activities documented a significantly lower mean value in patients than in asymptomatic carriers, suggesting a more complex mode of inheritance. To account for these findings, we tested a multiallelic inheritance model in one EPP family in which the enzymatic data were compatible with this hypothesis. In this EPP family, the specific FC gene mutation was an exon 10 skipping (delta Ex10), resulting from a G deletion within the exon 10 consensus splice donor site. The segregation of all FC alleles within the family was followed using the delta Ex10 mutation and a new intragenic dimorphism (1520 C/T). mRNAs transcribed from each FC allele were then subjected to relative quantification by a primer extension assay and to absolute quantification by a ribonuclease protection assay. The data support the hypothesis that in this family the EPP phenotype results from the coinheritance of a low output normal FC allele and a mutant delta Ex10 allele.     

Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia

Myoclonus-dystonia (M-D) is a movement disorder characterized by rapid muscle contractions and sustained twisting and repetitive movements and has recently been associated with mutations in the epsilon-sarcoglycan gene (SGCE). The mode of inheritance is autosomal dominant with reduced penetrance upon maternal transmission, suggesting a putative maternal imprinting mechanism. We present an apparently sporadic M-D case and two patients from an M-D family with seemingly autosomal recessive inheritance. In both families, we detected an SGCE mutation that was inherited from the patients' clinically unaffected fathers in an autosomal dominant fashion. Whereas, in the first family, RNA expression studies revealed expression of only the mutated allele in affected individuals and expression of the normal allele exclusively in unaffected mutation carriers, the affected individual of the second family expressed both alleles. In addition, we identified differentially methylated regions in the promoter region of the SGCE gene as a characteristic feature of imprinted genes. Using a rare polymorphism in the promoter region in a family unaffected with M-D as a marker, we demonstrated methylation of the maternal allele, in keeping with maternal imprinting of the SGCE gene. Loss of imprinting in the patient with M-D who had biallelic expression of the SGCE gene was associated with partial loss of methylation at several CpG dinucleotides.     

Burden of hereditary diseases in residents of the Sakh republic (Iakutiia)

Summarized data of medical genetic survey of the population of Republic of Sakha (Yakutia) are presented. The number of the population examined constituted 1000700 individuals (including 424500000 of urban and 576,200 of rural population, respectively). Regarding the ethnicity, 33 regions of the Republic examined were at most inhabited by Yakuts (36%) and Russians (55%). A total of 400 families (606 patients) with autosomal dominant, 274 families (369 patients) with autosomal recessive, and 42 families (53 patients) with X-linked pathologies were detected. The segregation analysis performed showed good correlation with the expected type of inheritance for both dominant and recessive diseases. The prevalence rate of monogenic hereditary diseases for rural and urban populations, as well as for solely Yakuts, was calculated. It was shown that weighted average prevalence of dominant (0.68; 1.44) and recessive (0.43; 0.86) disorders in Yakuts was two times higher than in total population examined.     

Genetic analysis of juvenile periodontitis in families ascertained through an affected proband.

Data from 28 families ascertained through a proband with juvenile periodontitis were used to test a series of Mendelian models of inheritance that included both autosomal and X-linked transmission. There was strong evidence of familial aggregation of this progressive dental disease, and the best-fitting model was an autosomal recessive model. Because of the rather limited age range for expression of the disease in this situation, simulations were done, in a model-choice analysis using samples of this size, to assess the chance of mistaking an autosomal dominant disease (with masking of the affected phenotype outside a specified age range) for an autosomal recessive disease. While the rate of Type II error was fairly high (40%) when competing models in these simulations were compared, these data suggest that it is reasonable to infer that juvenile periodontitis is an autosomal recessive disorder.     

The Load of Hereditary Diseases in the Population of Republic of Sakha (Yakutia)

Summarized data of medical genetic survey of the population of Republic of Sakha (Yakutia) are presented. The number of the population examined constituted 1 000 700 individuals (including 424 500 of urban and 576 200 of rural population, respectively). Regarding the ethnicity, 33 regions of the Republic examined were at most inhabited by Yakuts (36%) and Russians (55%). A total of 400 families (606 patients) with autosomal dominant, 274 families (369 patients) with autosomal recessive, and 42 families (53 patients) with X-linked pathologies were detected. The segregation analysis performed showed good correlation with the expected type of inheritance for both dominant and recessive diseases. The prevalence rate of monogenic hereditary diseases for rural and urban populations, as well as for solely Yakuts, was calculated. It was shown that weighted average prevalence of dominant (0.68; 1.44) and recessive (0.43; 0.86) disorders in Yakuts was two times higher than in total population examined.     

Progressive myoclonus epilepsy

Summary The syndrome of myoclonus, epilepsy, and mental deficiency is observed in a number of distinct nosologic entities differing with respect to clinical course, (-) pathologic, and biochemical findings. Genetically, the heterogeneity within this group of disorders is shown by the occurrence of autosomal recessive and dominant forms with incomplete penetrance. In this paper we report on a sibship with at least four affected males suffering from progressive myoclonus epilepsy, ataxia, and mental deterioration. The syndrome is probably X-linked, as suggested by the maternal transmission and mild, variable symptoms in some female carriers. In a survey of the literature we have found another pedigree suggesting X-linked inheritance of this variant of progressive myoclonus epilepsy.     

Antithrombin III deficiency: a report of 14 cases belonging to three different kindreds

A hereditary deficiency of AT III is described in 14 subjects belonging to three different kindreds. There is no consanguineity in any of the families investigated. The pattern of inheritance of defect appears autosomal dominant. Seven of the affected subjects presented thrombotic episodes (deep vein thrombosis, splanchnic thrombosis, pulmonary embolization). The main laboratory features were: normal routine clotting tests, decreased AT III activity in all assay systems and concomitantly reduced AT III antigen levels. Crossed immunoelectrophoresis showed only reduced peaks with respect to normal in both plasma and serum. No correlation was found between age of patients and AT III levels.     

A three generations family with blepharo-naso-facial malformations suggestive of Pashayan syndrome

Blepharo-naso-facial syndrome, described by Pashayan et al. (10), is characterized by telecanthus, lateral displacement and stenosis of lacrimal puncta, bulky nose, mask-like facies, trapezo?dal upper lip, torsion dystonia and mental retardation. We report on a family with this rare malformation syndrome, confirming the existence of this syndrome and its dominant inheritance. The proband had a fleshy nose, a prominant nose bridge, an hypoplastic midface, telecanthus with temporal displacement of puncta, lacrimal excretory obstruction. CNS torsion dystonia, increased deep tendon reflexes, Babinski reflexes, poor coordination and joint laxity. The proband's mother, brother and maternal grandfather also showed manifestations of the syndrome. The proband and his brother had delayed developmental milestones. Hearing impairment was present in the proband, his mother and his grandfather but was absent in the proband's brother. The blepharonasofacial syndrome was described by Pashayan et al. (10) in four members of one family, two male and one female sib and their mother. Two other sibs were unaffected. Many of the features of the blepharo-facio-nasal syndrome also occur in other well known syndromes i.e. Waardenburg syndrome. The pedigrees of the family of Pashayan et al. (10) and of our family are compatible with Mendelian dominant inheritance, either autosomal or X-linked. X-linked dominant inheritance cannot be ruled out except by male-to-male transmission, which does not occur in these families. Pashayan et al. (10) suggested that an autosomal gene with variable expressivity appears more likely. More families are needed for defining the transmission of the condition and for mapping the gene involved in the blepharo-naso-facial syndrome.     

Male-to-male transmission of the velo-cardio-facial syndrome: a case report and review of 60 cases

The velo-cardio-facial syndrome is one of the most common syndromes of clefting. Previous reports have shown vertical pedigree transmission, but in all cases the gene was maternally transmitted. The genetics of this syndrome had been suspected as autosomal dominant, but X-linked dominant inheritance could not be ruled out. This report describes an instance of male-to-male transmission of the velo-cardio-facial syndrome. In addition, the clinical findings in 60 cases are reported to further delineate the phenotypic spectrum of the syndrome.     

Tricho-rhino-phalangeal syndrome

Summary The case of a 13-year-old girl with tricho-rhino-phalangeal syndrome is presented. It is characterized by sparse and slow growing hair, pear-shaped nose and coneshaped epiphyses of hands and feet. The inheritance pattern is probably autosomal dominant transmission.