Microdeletion syndromes disclose replication timing alterations of genes unrelated to the missing DNA

<p>Abstract</p> <p>Background</p> <p>The temporal order of allelic replication is interrelated to the epigenomic profile. A significant epigenetic marker is the asynchronous replication of monoallelically-expressed genes versus the synchronous replication of biallelically-expressed genes. The present study sought to determine whether a microdeletion in the genome affects epigenetic profiles of genes unrelated to the missing segment. In order to test this hypothesis, we checked the replication patterns of two genes – <it>SNRPN</it>, a normally monoallelically expressed gene (assigned to 15q11.13), and the <it>RB1</it>, an archetypic biallelically expressed gene (assigned to 13.q14) in the genomes of patients carrying the 22q11.2 deletion (DiGeorge/Velocardiofacial syndrome) and those carrying the 7q11.23 deletion (Williams syndrome).</p> <p>Results</p> <p>The allelic replication timing was determined by <it>fluorescence in situ hybridization </it>(FISH) technology performed on peripheral blood cells. As expected, in the cells of normal subjects the frequency of cells showing asynchronous replication for <it>SNRPN </it>was significantly (P < 10^-12) higher than the corresponding value for <it>RB1</it>. In contrast, cells of the deletion-carrying patients exhibited a reversal in this replication pattern: there was a significantly lower frequency of cells engaging in asynchronous replication for <it>SNRPN </it>than for <it>RB1 </it>(P < 10^-4and P < 10^-3for DiGeorge/Velocardiofacial and Williams syndromes, respectively). Accordingly, the significantly lower frequency of cells showing asynchronous replication for <it>SNRPN </it>than for <it>RB1 </it>is a new epigenetic marker distinguishing these deletion syndrome genotypes from normal ones.</p> <p>Conclusion</p> <p>In cell samples of each deletion-carrying individual, an aberrant, reversed pattern of replication is delineated, namely, where a monoallelic gene replicates more synchronously than a biallelic gene. This inverted pattern, which appears to be non-deletion-specific, clearly distinguishes cells of deletion-carriers from normal ones. As such, it offers a potential epigenetic marker for suspecting a hidden microdeletion that is too small to be detected by conventional karyotyping methods.</p

Familial central precocious puberty suggests autosomal dominant inheritance

The prevalence of precocious puberty is higher in certain ethnic groups, and some cases may be familial. The aim of this study was to investigate the mode of inheritance of familial precocious puberty and to identify characteristics that distinguish familial from isolated precocious puberty. Of the 453 children referred to our center for suspected precocious puberty between January 1, 1997, and December 31, 2000, 156 (147 girls and 9 boys) were found to have idiopathic central precocious puberty, which was familial in 43 (42 girls and 1 boy) (27.5%). Data of the familial and sporadic cases were compared. The familial group was characterized by a significantly lower maternal age at menarche than the sporadic group (mean, 11.47 ؎ 1.96 vs. 12.66 ؎ 1.18 yr; P ‫؍‬ 0.0001) and more advanced puberty at admission (Tanner stage 2, 56.5% vs. 78.1%; P ‫؍‬ 0.006). Segregation analysis was used to study the mode of inheritance. The segregation ratio for precocious puberty was 0. (1) demonstrated that puberty may occur at an earlier age than previously thought, with a rate of early puberty four times higher in African-American girls than in Caucasian girls. This observation suggested a genetic regulation of the timing of puberty. Some pediatric endocrinologists believe that the pubertal pattern may be influenced by familial trends, such that families with one member with precocious puberty have a higher than normal probability of having another. However, scientific support for this assumption remains sparse. We found only a few published descriptions of cases of familial central precocious puberty (2-6) and only one study (3) of the prevalence of familial cases in a series of 58 patients with central precocious puberty. In the present study, we sought to determine the mode of inheritance of familial precocious puberty (FPP) in families with central precocious puberty and to identify specific clinical or laboratory features that distinguish familial from sporadic cases. We also calculated the prevalence of FPP at our tertiary care center in a given period of time. Patients and Methods Patients Of the 453 children evaluated in our clinic for precocious secondary sexual development between January 1, 1997, and December 31, 2000, 156 were found to have idiopathic central precocious puberty. The rest presented with precocious adrenarche (n ϭ 101), early puberty (n ϭ 89), premature thelarche (n ϭ 58), obesity associated with pseudothelarche (n ϭ 19), and other diagnoses (n ϭ 26); four were lost to follow-up. The diagnosis of precocious puberty was based on the presence of secondary sexual characteristics before age 8 yr in females and 9 yr in males. In girls, central precocious puberty was diagnosed on the basis of clinical characteristics, including appearance of breast buds before 8 yr of age accompanied by the presence of one or more of the following findings: menses, pubic hair, accelerated growth velocity, or bone age greater than 2 sd above chronological age. When the clinical picture was not obvious, the patients were followed for at least 6 months before the diagnosis was made. Adopted girls were excluded, as were girls with chronic disease, bone dysplasia, organic brain disease, congenital adrenal hyperplasia or other endocrinological abnormalities, and girls who had received radiation therapy and/or chemotherapy. Written informed consent was obtained from all families. The study was approved by the institutional human research committee. Methods At the first visit, the pedigree was determined, detailing medical illnesses and timing of puberty in family members. The parents completed a structured questionnaire including items on puberty in first-, second-, and third-degree relatives, and they were asked to contact directly the children&apos;s grandparents, aunts, uncles, and cousins to determine the age of puberty directly from them. We collected the data by contacting the parents by phone. First-degree relatives were defined as mother, father, brother(s), and sister(s); second-degree relatives as grandparents, aunt(s), and uncle(s); and third-degree relatives as cousins. Females were asked about age at appearance of breast buds and age at menarche and males about age at onset of pubertal changes and age at initiation of full-face shaving. Those who met the following criteria were included in the study group of FPP: 1) presentation with gonadotropin-dependent central precocious puberty, as described above; and 2) at least one of the following: menarche at age 10 yr or earlier in a first-, second-, or third-degree female relative; clinically documented precocious puberty, as described above, in a first-, second-, or third-degree relative; or full puberty, including full facial shaving, earlier than age 13 yr in a first-, second-, or third-degree male relative. [For Jewish males, age 13 (bar mitzvah) is a significant and well-remembered milestone.] Girls with idiopathic central precocious puberty without a family history were considered to have sporadic precocious puberty (SPP). All patients underwent clinical, biochemical, and bone age evaluation on admission. Pubertal stage was determined according to Marshall and Abbreviations: BMI, Body mass index; FPP, familial precocious puberty; SDS, sd score; SPP, sporadic precocious puberty. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community

A Locus for an Autosomal Dominant Form of Progressive Renal Failure and Hypertension at Chromosome 1q21

Linkage studies were performed in a large family with an autosomal dominant phenotype characterized by nephropathy and hypertension. In this family of Iraqi Jewish origin, the nephropathy develops into progressive renal failure. By performing a genomewide linkage search, we localized the disease gene to chromosome 1q21; the highest LOD score was obtained for the marker at locus D1S305, which yielded a maximum LOD score of 4.71 at a recombination fraction of 0. Recombination mapping defined an interval of ∼11.6 cM, between the markers at loci D1S2696 and D1S2635, that contains the disease gene. Localization of the disease-causing gene in this family represents a necessary step toward isolation of the defective gene and toward a deeper understanding of the mechanisms of hypertension and progressive renal failure