MYH9相关综合征家系的临床表型和遗传学分析

目的 分析1组MYH9相关综合征家系的临床表现及遗传学特征.方法我们随访到1组4代51人的MYH9相关综合征家系,对目前存活的46人进行了临床表型和遗传学的初步分析.结果家系内有MYH9相关综合征患者17人,实验室检测都具有典型的"血小板减少、巨大血小板和粒细胞包涵体"三联症;临床表现具高度复杂性.并伴有严重的白血病、青光眼、转氨酶升高、血脂升高、哮喘、鼻炎及白内障等多种疾病,除此之外,本家系大部分感染者都有鼻炎和哮喘过敏史,而且当上述症状发作时,患者身上的出血点或紫癜会明显加重;在遗传方式上属于常染色体显性遗传.从细胞遗传学水平对家系中成员进行染色体检查,未发现核型异常.结论该MYH9相关综合征家系属常染色体显性遗传,染色体检查未发现核型异常;家系中的感染者不仅具有巨大血小板、血小板减少及中性粒细胞包涵体的特性,而且还具有严重的如:肝炎、白内障、白血痛、哮喘等临床表现.     

A novel mutation in the <Emphasis Type="Italic">VHL</Emphasis> gene in a Chinese family with von Hippel-Lindau disease

Background

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome, and VHL is identified as a tumor suppressor gene. The main objective of this study was to identify disease-causing mutations in a Chinese family affected with VHL disease.

Methods

Genomic DNA was extracted from peripheral blood from a Chinese family with VHL. A predicted pathogenic variant was identified by targeted exome capture technology and next-generation sequencing.

Results

A novel heterozygous mutation (c.349?T?>?A, p.W117R) was detected in affected family members. No mutation was detected in unaffected family members or in the 150 normal controls. The mutation segregated with the disease phenotype throughout three generations. Histopathological examination revealed the characteristics of hemangioblastoma.

Conclusions

A novel W117R was detected in the VHL gene that caused retinal hemangioblastomas in affected members of a Chinese family.

     

Myotonic dystrophy: HLA antigens and mitogen stimulated lymphocyte responses of a Black American family

A Black American family of four generations with 29 members was studied. Six family members spanning two generations were affected with myotonic dystrophy. HLA A, B, C and DR antigen specificities were determined for each family member using local typing trays. Twelve HLA haplotypes were identified in the family. No significant association was found between the disease and any HLA antigenic type or haplotype. This finding suggests that the involvement of the major histocompatibility complex in the etiology of myotonic dystrophy is unlikely.
The cellular responses of twenty-eight family members and 20 unrelated Black Americans to phytohemagglutinin (PHA), Concanavalin A (Con A) and pokeweed mitogen (PWM), each in three concentrations, were tested with mononuclear cells prepared from peripheral blood. There was a significant difference in responses of the affected family members as compared to the unaffected family members and the unrelated Black Americans. The PHA and PWM responses of the unaffected family members are not significantly different from those of the unrelated Black American controls; however, the Con A responses of the unaffected family members are significantly higher than those of the control group at the lowest Con A dosage. The possible systemic defects of cytoskeletal structures of the affected family members are discussed.     

Patterns of family communication and preferred resources for sharing information among families with a Lynch syndrome diagnosis

Objectives

To explore patterns of communication among families with a Lynch syndrome diagnosis and understand what resources could facilitate family communication.

Oto-Palato-Digital syndrome in four generations of a larqe family

A new large family, affected by O-P-D syndrome is reported. Nine members in four consecutive generations have been studied. Computerized tomography study of spine and skull showed abnormalities to be confined to mesodermal derivates, while nervous structures were normal. Transmission pattern may be X-linked with intermediate expression in the female or autosomal dominant with sex limitation of expression.     

Cytogenetic and molecular characterization of a three-generation family with chromosome 5p terminal deletion

Terminal or interstitial deletion on the short arm of chromosome 5 is associated with a genetic disorder, cri-du-chat syndrome (cat cry syndrome), which is characterized by a cat-like cry in infancy, facial dysmorphism, microcephaly, and mental retardation. There is a high degree of variation in clinical presentations of patients with cri-du-chat syndrome, which is usually associated with different sizes and locations of deletions in chromosome 5p. Most patients with a 5p deletion have de novo mutations; familial 5p deletion is rare in literature. Here, we report a three-generation family with a 5p terminal deletion. The terminal 5p deletion (5p15.2-pter) in this family was confirmed and characterized by karyotyping analysis, fluorescent in situ hybridization, array comparative genome hybridization, and quantitative polymerase chain reaction. Although the affected family members apparently share deletions of the same size, there are some variations in mental symptoms within this family. Two affected females manifest moderate mental retardation and psychotic symptoms such as delusion of persecution, auditory hallucination, self-talking, and self-laughing, which are rare in cri-du-chat syndrome. In contrast, the other three affected males express mild-to-moderate mental retardation but no psychotic symptoms. Our study suggests that other factors besides the size and location of 5p deletions may modify the mental presentations of patients with 5p deletions.     

汉族FBN1基因突变所致马凡综合征一家系心血管表现的性别差异

 目的 通过分析一汉族马凡综合征家系多名患病成员的心血管系统受累表现与原纤维蛋白-1（FBN1）基因突变位点,提高对马凡综合征临床表现性别差异的认识。方法 收集一马凡综合征家系成员的心血管系统受累资料。在知情同意基础上采集外周血,提取基因组DNA,PCR扩增FBN1基因全部65个外显子及外显子内含子交界区,产物纯化后行Sanger法测序。结果 该家系共13名患者,所有9名存活患者均携带有c.5431G>A (p.Glu1811Lys)突变,而家族中正常个体无此突变。9名男性中4例猝死,另4名存在升主动脉扩张,1名表现为扩张性心肌病;4名女性中因心力衰竭死亡1例,另3名存在严重二尖瓣病变而无升主动脉扩张。结论 FBN1突变所致马凡综合征心血管系统受累即使是在同一家系中亦可表现为显著的差异。     

Deletion of the last two exons of FGF10 in a family with LADD syndrome and pulmonary acinar hypoplasia

Pulmonary acinar hypoplasia (PAH) and lacrimo-auriculo-dento-digital (LADD) syndrome have both been associated with loss-of-function variants in, or deletions of FGF10. Here we report a multi-generational family with seven members manifesting varying features of LADD syndrome, with one individual dying in early infancy of PAH. Whole genome sequencing in one family member identified a 12,158 bp deletion on chromosome 5p12 that removes two of the three exons of FGF10. Allele-specific PCR demonstrated that all affected family members, including the individual with PAH, carried the 12 kb deletion. We conclude the deletion is pathogenic and expands the mutational spectrum of FGF10 variants in LADD syndrome. The common mechanism underlying the variable clinical features of LADD syndrome is defective terminal branching of salivary and lacrimal glands and pulmonary acini, regulated by the TBX4-FGF10-FGFR2 pathway. The variable phenotypic expressivity of FGF10 haploinsufficiency from relatively benign to lethal is likely due to variation at other genetic loci.Subject terms: Genetics research, Respiratory tract diseases     

Myotonic dystrophy and limb girdle muscular dystrophy in one family

A family is reported in which a 29-year-old woman showed the clinical features of myotonic dystrophy while her 26-year-old brother presented with the clinical picture of limb girdle syndrome. In the affected female, direct genetic testing for the specific myotonic dystrophy mutation on chromosome 19 revealed abnormal expansion of a repeat unit containing the three nucleotides cytosine, thymine, and guanine (CTG) — typical for myotonic dystrophy — while her diseased brother displayed two normal alleles. This supports the hypothesis of the extremely rare occurrence of two clinically and genetically different myopathies in one family. Genetic analysis of six other family members showed that the father of the diseased siblings as well as all of his three brothers and sisters had a pathological CTG repeat expansion, and that the other two family members tested had a normal allelic pattern. The number of CTG repeats in the diseased women was approximately tenfold higher than in her asymptomatic relatives who revealed an abnormal allelic pattern. The increase in CTG repeats with transmission to a subsequent generation in this family was paralleled by a dramatic increase in the severity of myotonic dystrophy.Abbreviations DM myotonic dystrophy - LGS limb girdle syndrome - LGMD limb girdle muscular dystrophy - CTG cytosine, thymine, guanine - PCR polymerase chain reaction     

Clinical aspects of the MASA syndrome in a large family, including expressing females

We have evaluated, both clinically and by linkage analysis, a large family with 22 known affected males with the MASA syndrome (McKusick 303300). Clinical findings varied widely amongst the affected family members, with some appearing initially to have the MASA syndrome and others to have X-linked hydrocephalus (HSAS) (McKusick 307000). Important findings included the presence of adducted thumbs in two obligate carriers, learning problems or mild mental retardation in three females, two of whom were obligate carriers, and hydrocephalus with neonatal death in three females born to obligate carriers. X-inactivation analysis in lymphocytes from the two women with adducted thumbs revealed preferential inactivation of one X chromosome, suggesting that nonrandom X-inactivation may be responsible for clinical expression in females. The presence of HSAS in some individuals of this family and the MASA syndrome in others further supports the hypothesis that these two conditions are the result of a mutation in the same gene.     

A new Spanish family with Hb Louisville

The clinical, hematological, and biochemical characteristics of a new family with heterozygous hemoglobin (Hb) Louisville are described. The family showed a decrease in both oxygen affinity and cooperativity with the normal Bohr effect. This family has the greatest number of affected members reported to date. Among the descendants, two first cousins (III-10 and III-11), both of whom are affected by the heterozygous trait of Hb Louisville, had had three abortions of undetermined causes.     

Manifestations in a family with autosomal dominant bone fragility and limb-girdle myopathy

We report on an unusual family with an autosomal dominant limb-girdle type of myopathy and bone fragility. This family was previously reported by Henry et al. [1958] as autosomal dominant progressive limb girdle "muscular dystrophy" with propensity to fractures and defective healing of long bones. Clinical, biochemical, and radiological aspects were evaluated in eight living relatives in this family (three males and five females) and in eight deceased individuals. The average age-of-onset of the limb-girdle myopathy was 31 years occurring in 87% of affected individuals. The average age of onset of fractures was 24 years occurring in 88% of affected individuals. Biochemical analysis showed a mean alkaline phosphatase (ALP) of 64 U/L (normal 30-120) and borderline high creatine kinase (CK) of 213 U/L (normal 4-220). Radiographs revealed coarse trabeculation, patchy sclerosis, cortical thickening, and narrowing of the medullary cavity with an appearance not considered typical of Paget disease of bone (PDB) or of fibrous dysplasia. Results of nerve conduction studies were normal, and electromyograms and muscle biopsies documented non-specific myopathic changes. There is premature graying with thin hair, thin skin, hernias and the affected individuals appear older than their chronological age, and three members had a clotting disorder. Linkage analysis for markers for the chromosome 9p22.3-q12 locus indicated that the disorder in this family does not segregate with markers in the critical region of limb-girdle/inclusion body myopathy, PDB, and frontotemporal dementia (FTD) [IBMPFD, OMIM #605382]. Sequencing of Valosin-containing protein (VCP), the gene associated with IBMPFD, did not identify mutations. We have excluded linkage to the known loci for limb-girdle type of myopathy and bone disease and excluded several candidate genes. Elucidation of the novel molecular basis of this disorder may provide valuable links between bone, collagen and muscle, and targeted therapeutic options.     

Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome

Deafness and onychodystrophy is a presumed autosomal dominant condition previously reported in five families. We report on a three-generation family with three affected members with absent finger and toenails, finger-like thumbs, and severe sensorineural deafness. In the hands, the first and fifth digits had absent nails and bulbous swelling of the distal phalanx. The second, third, and fourth digits were relatively spared. In the feet,there were hypoplastic great toenails and absent nails on second to fifth toes. Intelligence was normal. In addition to deafness and onychodystrophy, other features in this family included subtle facial dysmorphism in two individuals, cutis aplasia in one individual, epilepsy in one individual, and sudden infant death in two family members, one of whom had deafness and onychodystrophy and one who did not. A full autopsy of both infants did not reveal a cause. SNP microarray analysis of one family member showed no evidence of copy number change. This family's condition fits within the spectrum of dominant deafness-onychodystrophy syndrome (DDOD) and further characterises this rare condition.     

Immunoglobulin concentration and Gm allotypes in a family with thirty-three cases of myotonic dystrophy

Serum IgG, IgA, and IgM concentrations were measured in 120 members of a family with 33 cases of Dystrophia myotonica (Dm) and 27 members who were "possibly affected". The Dm individuals had significantly lower serum concentrations of IgG and IgA (P<0.01), while the "possibly affected" did not differ from the matched pair controls. IgG subclass concentrations were measured and Gm and Am types determined. The lower concentration of IgA in the affected individuals was not associated with a particular Am type. The concentration of IgG3 was barely lower in the affected than in the controls (P=0.05), but there were no differences for IgGl. When IgG3 concentration was compared according to Gm haplotype, only the two affected individuals who were Gm gg had a statistically significant lower concentration than the 12 controls (P<0.02). Thus, there is no evidence that a particular subclass of IgG is being hypercatabolized in our Dm patients. A rare Gm haplotype, Gm(-, n, b) had entered the family with two brothers; it is not known whether this codes for an IgGl-IgG3 hybrid molecule or a normal IgGl molecule with an unknown Gm allele or a yl deleted Gm haplotype.     

Renal-coloboma syndrome: prenatal detection and clinical spectrum in a large family

Renal-coloboma syndrome includes abnormalities in the urogenital and ocular systems as its primary manifestations, although it can be associated with abnormalities in other systems as well. This syndrome is caused by mutations in the PAX2 gene and is transmitted as an autosomal dominant trait. We report a family in which at least 7 members have manifestations of renal-coloboma syndrome, including two in whom renal disease was diagnosed prenatally by ultrasound examination. A pathogenic frame-shift mutation (619insG) was found in the PAX2 gene in affected family members, who show remarkable variability in both the ocular and renal manifestations of the syndrome.     

A family with mental retardation, variable macrocephaly and macro-orchidism, and linkage to Xq12-q21.

A family with X linked inheritance of mental retardation (XLMR) is presented. There are 10 mentally retarded males and two affected females in two generations. There are four obligatory carriers, one of whom is described as "slow". Most affected males show macrocephaly and macro-orchidism, which are typical signs of the fragile X syndrome, but have been tested cytogenetically and by analysis of the FMR1 gene and do not have this syndrome. However, some normal males in the family also exhibit macro-orchidism and macrocephaly. Linkage analysis using markers derived from the X chromosome indicates that the causative gene in this family is located in the proximal long arm of the X chromosome, in the interval Xp11-q21. Maximum lod scores of 2.96 with no recombination were found at three loci in Xq13-q21: DXS1111, DXS566, and DXS986. Recombination was observed with DXS1002 (Xq21.31) and DXS991 (Xp11.2), loci separated by about 30 Mb. Although isolation of the gene in this family will be difficult because of the size of the region involved, the localisation should be helpful in investigating other similar families with XLMR, macrocephaly, and macro-orchidism not attributable to FMR1.     

A family with congenital suprabulbar paresis (Worster-Drought syndrome)

A three generation family is described in which four members were found to have congenital suprabulbar paresis (Worster-Drought syndrome). It is suggested that some cases of congenital suprabulbar paresis are inherited as an autosomal dominant trait with variable expression and penetrance.     

A family with craniofrontonasal dysplasia, and fragile site 12q13 segregating independently

Coronal craniosynostosis, hypertelorism, telecanthus, broad grooved nasal tip, dental anomalies, mild syndactyly and broad thumbs, consistent with craniofrontonasal dysplasia are described in a family of four affected females over three generations. Documentation of the family is of interest because of variable clinical features and an excess of affected females. The excess of females observed in this condition is as yet unexplained, but cannot be referred simply to X-linked dominance with lethality in the male. Autosomal dominance with less frequent and less severe expression in the male is more tenable. Chromosome analysis on two affected family members revealed a fragile site at 12q13, which was also found in a phenotypically normal family member. A third affected individual did not exhibit this fragile site. Thus it appears that there is a heritable fragile 12q13 site segregating in this family separately from the gene for craniofrontonasal dysplasia.     

Simpson-Golabi-Behmel syndrome: follow-up of the Michigan family

Here we report a follow-up on a boy born in 1983 into a family with presumed Simpson-Golabi-Behmel syndrome and first reported as patient 3 by Opitz [1984] under the designation "Golabi-Rosen" syndrome. The patient died at 25 months without having attained any measure of psychomotor development or maturation and with a neurologic picture of irritability, increased muscle tone, seizures, deafness and possible cortical blindness. He had a striking facial appearance similar to that of severely affected individuals in the family reported by Golabi and Rosen [1984], with mild hepatosplenomegaly, unusual skin, normal growth, decelerating OFC, and on autopsy a spongiform degeneration of brain stem and cerebrum. Results of all biochemical studies, including those pertaining to GM3 gangliosidosis, were normal.