Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth.

Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5' donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth.

Using FISH to increase the yield and accuracy of karyotypes from spontaneous abortion specimens.

OBJECTIVE: Cytogenetic analysis of spontaneous abortions is frequently complicated by culture failure and maternal cell contamination (MCC). The objective of the study is to demonstrate that multiplex fluorescence in situ hybridization (FISH) can increase the yield and accuracy of karyotypes from spontaneous abortion specimens. METHOD: A multiplex interphase FISH probe set was used to analyze two sample sets. (1) Uncultured tissues from 153 abortions samples with a normal 46,XX karyotype and (2) a series of 171 samples that either failed to grow or were contaminated. MCC studies were performed on 70 cultures where both karyotype and FISH indicated a normal female karyotype. RESULTS: FISH showed 31% (53/171) of the specimens karyotyped as 46,XX were either male or abnormal; 23% (40/118) of these specimens were found to have an abnormal chromosome complement. In specimens with culture failure, FISH showed an abnormal complement in 44.4% (68/153). MCC studies showed 41.49% (29/70) cultures of maternal origin, 45.7% (32/70) fetal, 11.4% (8/70) a maternal/fetal mixture and 1 diploid mole. CONCLUSION: Results demonstrate the utility of a simple FISH panel in increasing the detection rate of abnormal karyotypes. They also reveal the high frequency of overgrowth of maternal cells in cultured specimens from villi after embryonic loss.

Multiplex interphase FISH as a screen for common aneuploidies in spontaneous abortions.

BACKGROUND: A multiplex fluorescence in-situ hybridization (FISH) strategy using chromosome-specific probes for eight chromosomes as an initial screen for chromosome abnormalities in uncultured tissues from spontaneous abortions was evaluated. METHODS: Fifty-seven prefetal spontaneous abortions were studied by karyotyping cultured cells and using FISH on uncultured cells. Two probe sets were used, identifying chromosomes 13, 15, 16, 18, 21, 22, X and Y. RESULTS: Abnormalities were detected in 53% of cases by karyotyping, and 54% of cases by FISH. FISH detected an abnormality in four of five cases where cultures failed, and in two cases where maternal cells apparently overgrew the culture. FISH missed four trisomies not identifiable with the probe sets, and one trisomy because one probe set was unscorable. FISH using these probes identified 83% of all abnormalities detected by karyotyping. CONCLUSIONS: FISH can detect abnormalities in a significant proportion of cases where the culture fails to grow or is contaminated by maternal cell growth. Multiplex FISH as an initial screen, followed by culture and karyotyping in cases where no abnormality is detected, would identify a higher proportion of chromosome abnormalities in spontaneous abortion specimens than karyotype analysis alone.