中国人常染色体隐性遗传性多巴反应性肌张力障碍TH基因突变分析

目的　研究中国人常染色体隐性遗传性 (autosomal recessive,AR)多巴反应性肌张力障碍(dopa- responsive dystonia,DRD)患者酪氨酸羟化酶 (tyrosine hydroxylase,TH)基因的突变特点。方法　应用聚合酶链反应 -单链构象多态性技术和 DNA序列分析方法对 5个 AR- DRD家系的先证者和两例散发DRD患者进行 TH基因突变分析。结果　 TH基因第 1～ 2、5～ 11、13～ 14外显子的扩增产物未见异常电泳条带 ,DNA直接测序 TH基因的第 3、4、12外显子 ,结果未发现异常。结论　 TH 基因在中国人 AR-DRD家系中突变率不高 ,提示我国 AR- DRD患者具有遗传异质性 ,可能存在新的致病基因。     

Dyskeratosis congenita: an autosomal recessive variant

We describe a woman with dyskeratosis congenita (DKC), microcephaly, and a purple discoloration of the tongue. The latter findings are not commonly described in males with DKC, have been reported in another female patient with this condition, and may represent the phenotype of an autosomal recessive entity of DKC. Results of X chromosome inactivation studies did not support X-linked DKC in our family. The additional findings of an affected brother and parental consanguinity support the hypothesis of autosomal recessive inheritance.     

Lecithin-cholesterol-acyltransferase deficiency: autosomal recessive transmission in a large kindred*

Thirty-four members of a single Sardinian kindred with lecithin-cholesterol-acyltransferase deficiency have been studied. The kindred spans four generations and the parents of the two affected siblings are blood relatives. Segregation of the acyltransferase deficiency gene in the family clearly demonstrated an autosomal recessive mode of inheritance. Thirteen family members, including all obligate heterozygotes, had roughly half-normal acyltransferase activities (mean ± S.D. = 0.39 ± 0.06 mU/ml) when compared to 17 intrafamilial controls and spouses (mean ± S.D. = 0.72 ± 0.09 mU/ml) and 40 blood donors from Marburg/Lahn (mean ± S.D. = 0.76 ±0.1 mU/ml). Characterization of the heterozygotes did not reveal abnormalities in their plasma lipoproteins. LCAT deficiency and the β-thalassaemia trait coexisting in this kindred segregated independently.     

Renal-hepatic-pancreatic dysplasia: an autosomal recessive malformation.

We report two brothers with a cystic malformation of the kidneys, liver, and pancreas. In both cases the malformation was fatal and the children died shortly after birth. The pathological findings, consisting of multicystic dysplastic kidneys, dilated and dysgenetic bile ducts, dilated pancreatic ducts, and polysplenia, correspond to those reported by Ivemark as renal-hepatic-pancreatic dysplasia. Many polymalformation syndromes include cystic affectation of these three organs, so this syndrome could be an isolated entity or a final common pathway of response of these organs to a variety of developmental disturbances, which could also include splenic abnormalities. We propose an autosomal recessive pattern of inheritance for renal-hepatic-pancreatic dysplasia.     

Lysinuric protein intolerance, an autosomal recessive disease

Lysinuric protein intolerance (LPI) is characterized by failure to thrive, diarrhea and vomiting associated with protein intake, aversion to protein-rich food, growth retardation, hepatomegaly, hyperammonemia, and deficient urea formation after an amino nitrogen load, and increased urinary excretion of basic amino acids, especially lysine. LPI has been diagnosed in 16 patients of 10 families in Finland and in one Finnish immigrant in Sweden. In this study data were evaluated to test the autosomal recessive transmission of LPI.
In 6 families out of 10 the occurrence was familial. The sex ratio of those affected was 6 : 10. The proportion of affected sibs, corrected by Apert's a priori method, was 0.26. In 5 families the parental marriage was consanguineous, and in two groups of two families all four parents were descendants of one ancestor pair. The geographical distribution of the LPI ancestors was uneven as is true for many rare recessive diseases in Finland. No heterozygous effects of the LPI gene could be detected with certainty. These finclings constitute evidence in favor of the autosomal recessive transmission of LPI.     

Congenital chloride diarrhea, an autosomal recessive disease

Congenital chloride diarrhea (CCD) is a persistent, life-thieatening watery diarrhea with a uniquely high chloride concentration of stool water. It is manifested prenatally hy hydramnios. Evidence was sought to substantiate its genetic transmission as an autosomal recessive trait.
Genetic data on 12 families reported from outside Finland and 11 evident and 3 probable families in Finland are discussed. The occurrence was familial in at least 5 sibships. No sex-specificity was found. The corrected proportion of affected siblings was 0.18 -0.29 (extreme possibilities of ascertainment). The parental marriage was consanguineous in 3 evident and 3 probable families, and 17 out of 27 known parents were shown to be consanguineous with 1 -8 other CCD parents. The ancestors were unevenly distributed geographically, originating mainly from the eastern parts of Finland. These findings, taken with the peculiar population structure of Finland, constitute distinct evidence for the autosomal recessive mode of transmission of CCD.
The name congenital chloride diarrhea is advocated.     

Congenital generalized fibromatosis: an autosomal recessive condition?

Congenital generalized fibromatosis is a rare condition which is often misdiagnosed and given an erroneously poor prognosis. Five new cases are presented in this report, all initially having been diagnosed as neurofibromatosis. The histopathological findings are presented and the differential diagnosis is discussed. The natural history of the disorder appears to include an initial phase of proliferation soon after birth with appearance of new tumor masses. Providing these do not involve vital viscera, the patient survives with regression and eventual disappearance of all lesions. Spontaneous regression occurred in all five patients reported. Two sets of sibs occurred in the cases described. The possible genetic aspects of this are discussed and the pertinent literature reviewed.     

ZFP57 mutations cause an autosomal recessive imprinting disorder

Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57
Mackay et al. (2008)
Nature Genetics 40: 949–951     

Evidence for an autosomal recessive form of cleidocranial dysostosis

Three cases of cleidocranial dysostosis from two unrelated consanguineous families are reported. The family setting, the distribution of the affected members, plus the severity of involvement suggest that there is also an autosomal recessive form of this disorder.     

Ehlers-Danlos syndrome type IV D: an autosomal recessive disorder

Two siblings born to consanguineous parents are reported with typical clinical features of the Ehlers-Danlos syndrome type IV. However, their cultured skin fibroblasts synthesize and secrete procollagen type III in normal amounts and proportions. This is probably a new form of the Ehlers-Danlos syndrome with autosomal recessive inheritance classified as Ehlers-Danlos syndrome type IV D.     

Split-hand and split-foot deformity inherited as an autosomal recessive trait

A intermarried consanguineous family with split-hand and -foot deformity occurring in two sibship is presented. Both the sibship resulted from marriage between first cousins. This report, together with those of Ray (1960) and Freire-Maia (1971), further demonstrates that split-hand and -foot deformity can be inherited as an autosomal recessive trait.     

Identical twins with an autosomal recessive form of spondylocostal dysostosis

A form of spondylocostal dysostosis, marked by multiple vertebral clefts, costal bifurcation, and fusion was observed in identical male twins whose parents were first cousins. The lack of previous anomalies in the family, the high degree of parental inbreeding and the absence of deformities in a 3-year-old brother indicated an autosomal recessive mode of inheritance.     

Dentato-olivary dysplasia in sibs: an autosomal recessive disorder?

The cases of a brother and sister with dentato-olivary dysplasia are described. Both had severe developmental delay, severe epilepsy of early onset, evolving hypertonic quadriplegia, and death in early childhood. Postmortem examination of the brain in one child showed a particular form of dentato-olivary dysplasia. These children show many features in common with previously described cases of this condition, but this is the first report of occurrence in sibs.     

The prevention and management of autosomal recessive conditions. Main example: alpharantitrypsin deficiency

In populations in which a particular autosomal recessive disorder is treatable and relatively common, and for which there is a simple diagnostic test, newborns can be screened and treated. For some disorders, such as α₁-AT, young people can be screened and given appropriate advice to ameliorate the future symptoms. For some severe common and non-treatable autosomal recessive disorders, for example cystic fibrosis, carrier tests will probably soon be available for population screening of young people. Couples found to be carriers can then be offered prenatal diagnosis and termination of the pregnancy, in the fetus is affected. In the not-too-distant future the approaches will hopefully be treatment and correction of these disorders in the affected fetus or newborn.     

Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder

Purpose5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive.MethodsWe combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene.ResultsWe identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment.ConclusionOur data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.     

Tachycardia: an autosomal, monogenic, biallelic, recessive trait

A brief commentary of the genetics of blood pressure is presented. The importance of the mechanisms of blood pressure regulation, among which heart rate is relevant, is emphasized. The analysis of a small population to test the quantitative model of the trait heart rate, considered as a metric character, is presented. The analysis of heart rate fitting to a qualitative model of inheritance is carried out. The results displayed might support the hypothesis that tachycardia could be an autosomal, monogenic, biallelic recessive trait.     

Novel autosomal recessive progressive hyperpigmentation syndrome

We present a family of Iraqui origin with three siblings affected by a novel type of progressive hyperpigmentation syndrome. The generalized initially diffuse, later disseminated hyperpigmentation started in early infancy and increased during childhood. It also affected palms and soles, and the face but spared the cheeks. Additional features were dry, itchy and sunlight sensitive skin, dystrophy of toe nails, hair loss, and myopia, but normal sweat glands. Light and electron microscopy showed signs of pigment incontinence and compound melanosomes as well as fibrillar bodies. The occurrence of this entity in affected siblings from a consanguineous mating suggests autosomal recessive inheritance. Extensive review of the literature showed no previous report with this distinct combination of clinical and microscopic findings.     

Newly recognized autosomal recessive faciothoracoskeletal syndrome

We report on 2 brothers, born to consanguineous parents presenting thin/long face, small ears, blepharophimosis, malar hypoplasia, long nec, pectus excavatum, brachy-camptodactyly, and sacral dimple. We suspect that these patients represent a previously undescribed autosomal recessive syndrome. © 1994 Wiley-Liss, Inc.