X-性连锁鱼鳞病两家系基因检测及产前诊断

Genetic testing and prenatal diagnosis of X-linked ichthyosis in two pedigrees

目的对2个X-I生连锁鱼鳞病（X-linked ichthyosis，XLI）家系进行基因检测及胎儿产前诊断。方法应用染色体核型分析、细菌人工染色体标记一磁珠鉴别／分离技术（bacterial artificial chromosomes-on-Beads^TM，BoBS）、荧光原位杂交（fluorescence in situ hybridization，FISH）技术和微阵列单核苷酸多态性芯片（singlenucleotidepolymorphismarray，SNP—array）技术，对未知鱼鳞病家族史的家系1和已知鱼鳞病家族史的家系2的羊水及外周血标本进行基因检测及胎儿产前分子诊断，并收集相关临床资料。结果（1）家系1：产前BoBs方法检测到家系1胎儿（Ⅳ-12）XCl探针为0．36-0．50，提示存在微缺失。孕妇（Ⅲ-13）SNParray检测结果显示Xp22．31区域存在1．68Mb拷贝数缺失，丢失4个在线人类孟德尔遗传数据库（Online Mendelian Inheritancein Man，OMIM）基因（分别为HDHDl、STS、VCX和PNPLA4）。胎儿SNP-array结果为arr[hgl9]Xp22．31（6455151-8l35644）×0，提示缺失遗传自母亲。FISH分析的结果证实胎儿STS基因缺失，核型结果为46，XY。孕妇表妹（Ⅲ-21）及表外甥（1V-14）同样存在STS基因缺失，缺失大小与孕妇及胎儿一致。结果Ⅳ-12足月剖宫产出生，出生时皮肤未见异常，生后1周腹部出现白色鳞屑广泛附着，天气干燥时症状加重。对该例婴儿随访至8月龄，未发现其他临床症状。（2）家系2：SNParray结果显示，孕妇（Ⅲ-21）、先证者（Ⅳ-16）及胎儿（IV17）在Xp22．31区域存在1．2Mb拷贝数缺失，丢失4个OMIM基因（分别为HDHDl、STS、VCX和PNPLA4）。FISH结果验证家系2胎儿STS基因缺失。胎儿核型结果为46，XY。结果Ⅳ-17足月剖宫产出生，出生时皮肤未见异常；至10日龄时，腹部出现白色鳞屑广泛附着。对该例婴儿随访至4个月，未发现其他临床症状。结论联合运用BoBs、FISH和SNP-array等分子遗传学技术有助于XLI的诊断及遗传咨询。

Objective To analyze genetic testing and prenatal diagnosis of two pedigrees with X-linked ichthyosis. Methods Karyotyping, bacterial artificial chromosomes-on-BeadsTM （BoBs）, fluorescence in situ hybridization （FISH） and single nucleotide polymorphism array （SNP array） were used to detect amniotic fluid and peripheral blood specimens of two pedigrees, one with and one without known family history of ichthyosis. Clinical data was collected and analyzed as well. Results （1） The pedigree without known family history： Prenatal BoBs showed that the XC1 probe of fetus Ⅳ -12 was from 0.36 to 0.50, suggesting the presence of microdeletion. SNP-array analysis of gravida Ⅲ -13 showed a 1.68 Mb copy number deletion at Xp22.31 and four missing Online Mendelian Inheritance in Man （OMIM） genes （HDHD1, STS, VCX and PNPLA4）. Fetal SNP-array revealed a deletion of arr[hg 19] Xp22.31 （6 455 151-8 135 644）× 0, indicating a maternally inherited one. FISH analysis verified the deletion in STS gene in fetus IV -12, whose karyotype was 46, XY. The gravida＇s female cousin （ Ⅲ-21） and nephew （ Ⅳ -14） also had STS gene deletion, which size was the same as that from the gravida and the fetus. Fetus （ Ⅳ 12） was delivered at term by cesarean section with normal skin, but an extensive white scales appeared on the abdomen one week after birth and the symptom was aggravated when the weather was dry. The infant was followed up to eight months old and no other clinical symptoms were found. （2） The pedigree with known family history： SNP-array revealed that a 1.2 Mb copy number deletion at Xp22.31 and four missing OMIM genes （HDHD1, STS, VCX and PNPLA4） were detected in pregnant women （ Ⅲ-21）, proband （ Ⅳ -16） and fetus （ Ⅳ -17）. FISH analysis of the fetus verified the deletion in STS gene. The karyotype of the fetus was 46, XY. Fetus Ⅳ 17 was delivered at term by cesarean section with normal skin, but white scales widely appeared on the abdomen ten days after birth. The infant was followed up to four months old and no other clinical symptoms were found. Conclusion Molecular genetic techniques such as BoBs, FISH and SNP array are used in combination in this study to provide genetic testing and prenatal diagnosis to two XLI pedigrees, which is helpful for clinical diagnosis and genetic counseling.