A combined approach to the molecular analysis of cystinuria: from urinalysis to sequencing via genotyping.

BACKGROUND: Cystinuria is an autosomal recessive disease that is manifested by kidney stones and is caused by mutations in two genes: SLC3AI on chromosome 2p and SLC7A9 on chromosome 19q. Urinary cystine levels in obligate carriers are often, but not always, helpful in identifying the causative gene. OBJECTIVES: To characterize the clinical features and analyze the genetic basis of cystinuria in an inbred Moslem Arab Israeli family. METHODS: Family members were evaluated for urinary cystine and amino acid levels. DNA was initially analyzed with polymorphic markers close to the two genes and SLC7A9 was fully sequenced. RESULTS: Full segregation was found with the marker close to SLC7A9. Sequencing of this gene revealed a missense mutation, P482L, in the homozygous state in all three affected sibs. CONCLUSIONS: A combination of urinary cystine levels in obligate carriers, segregation analysis with polymorphic markers, and sequencing can save time and resources in the search for cystinuria mutations.

An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis.

Monilethrix is a structural defect of the hair shaft usually inherited in an autosomal dominant fashion and caused by mutations in the hHb1, hHb3, and hHb6 keratin genes. Autosomal recessive inheritance in this disease has been sporadically reported. We encountered 12 Jewish families from Iraq, Iran, and Morocco with microscopic findings of monilethrix, but with no evidence of vertical transmission. Since no mutations were found in these three hair keratin genes, we examined nine chromosomal regions containing gene clusters encoding skin and hair genes. On chromosome 18q, a common haplotype in the homozygous state was found among all seven Iraqi patients, but not in 20 controls (P<0.0001). Sequencing of the main candidate gene from this region revealed four different mutations in desmoglein 4 (DSG4). Mutations in DSG4 have been previously reported in localized autosomal recessive hypotrichosis, a disorder that shares the clinical features of monilethrix but lacks the characteristic microscopic appearance of the hair shaft. Our findings have important implications for genetic counseling to monilethrix patients and families, and suggest that DSG4-associated hair disorders may be more common than previously thought.

Patients' information needs and decision-making processes: what can be learned from genetic counselees?

This field study investigated the information needs and decision-making strategies of 161 genetic counselees interviewed just prior to counseling. Patients were interested mostly in information about the outcomes and consequences of the alternative options at their disposal and about measures to defuse the risks. They wanted mainly information stated with certainty and were less interested in probability information. There was no difference in the search for information between the alternative eventually chosen and the one not chosen. There was a difference, however, among types of decisions and the interest in the various categories of information. These findings were interpreted within the theoretical model of decision making in natural risky situations (O. Huber, 1997). Practical implications for shared medical decision making are presented.

The facilitating role of information provided in genetic counseling for counselees' decisions.

PURPOSE: To investigate genetic counselees' evaluations of the helpfulness of the information they receive in genetic counseling and of their difficulty in making decisions, and to determine correlates of these two outcomes. METHODS: A field study on 108 counselees seeking genetic counseling aimed at arriving at a reproduction-related decision. Prior to counseling, questionnaires measuring individual differences in factors expected to correlate with outcomes were administered. The objective controllability of the information conveyed in counseling was evaluated by counselors. The outcomes--decision difficulty and information helpfulness--were evaluated one month after counseling in a telephone interview. RESULTS: Information about consequences of options and about possible controlling actions were evaluated as most helpful; whether other information was helpful depended on the type of decision to be made. Decision difficulty was unrelated to counselees' evaluations of the helpfulness of the information. Decision difficulty was also unrelated to individual difference variables, but was related to the objective controllability of the information. CONCLUSION: These findings may help develop guidelines for identifying clients prior to counseling for whom making reproduction-related decisions will be difficult, and for tailoring information that will help such clients reach a decision.