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推送日期：2017.3.28 OMIM编号：270750 疾病：痉挛性截瘫23型 表型：childhood-onset spastic paraplegia（痉挛性截瘫） resulting in gait（步态） difficulties and associated with pigmentary（色素） abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions（病变）. 基因：DSTYK 背后的小故事：  In affected members of 3 unrelated families of Middle Eastern descent with SPG23, including the family reported by Mukamel et al. (1985) and Blumen et al. (2003), Lee et al. (2017) identified a homozygous intragenic deletion/insertion in the DSTYK gene (4-KB DEL AND 20-BP INS). The deletion, which was found by a combination of whole-exome sequencing, homozygosity analysis, and copy number variation analysis in the first family, segregated with the disorder in all 3 families. 游侠点评：该案例很好地诠释了NGS的优势，如果朋友们之前有家系定位至某染色体区间而不确定基因的，现在就是最好的时机去定位致病基因 OMIM编号：617402 疾病：皮肤松弛2C型 表型：generalized skin wrinkling with sparse subcutaneous（皮下） fat and dysmorphic progeroid （早老）facial features. Most patients also exhibit severe hypotonia as well as cardiovascular involvement。 基因：ATP6V1E1 背后的小故事：  In affected individuals from an Iranian family and a Kuwaiti family with cutis laxa, Van Damme et al. (2017) performed whole-exome sequencing and identified homozygosity for 2 different missense mutations in the ATP6V1E1 gene: L128P (108746.0001) in the Iranian family, and R212W (108746.0002) in the Kuwaiti family. 游侠点评：看人家两个小家系就发一篇AJHG，国内的朋友们加油啊！ OMIM编号：617403 疾病：皮肤松弛2D型 表型：generalized skin wrinkling with sparse subcutaneous fat and dysmorphic progeroid facial features. Most patients also exhibit severe hypotonia as well as cardiovascular and neurologic involvement. 基因：ATP6V1A 背后的小故事： In 3 probands with cutis laxa, including a 15-year-old German boy originally described by Van Asbeck et al. (2014), Van Damme et al. (2017) performed whole-exome sequencing and identified homozygous missense mutations in the ATP6V1A gene: the German boy was homozygous for an R338C substitution (607027.0001), and the Pakistani and Turkish male infants were both homozygous for a G72D substitution (607027.0002). The mutations segregated with disease in each family, and neither was found in in-house exome cohorts or in the ExAC database. 游侠点评：又是一个之前文章未确定致病基因，后面继续分析确定致病基因的案例 推送日期：2017.3.27 OMIM编号：617395 疾病：先天性糖基化异常2q型，CDG2Q 表型：early development in the first months of life, but presented around 8 months of age with delayed development, acquired microcephaly, and spastic quadriplegia. He developed generalized tonic seizures at age 10 months; brain imaging showed diffuse cerebral atrophy, thin corpus callosum, and small pituitary（垂体） gland. Laboratory studies showed liver dysfunction, hypocupremia（低铜血症）, and hypoceruloplasminemia（低铜蓝蛋白血症）, all of which resolved spontaneously by 3 years of age. Isoelectric focusing of serum transferrin and apolipoprotein C3 showed abnormal glycosylation: transferrin showed an increase of mono-sialo and a-galacto species, and apolipoprotein CIII showed a slight decrease of di-sialo and an increase of unglycosylated species. 基因：COG2 背后的小故事： In a 6-year-old boy, born of unrelated Japanese parents, with CDG2Q, Kodera et al. (2015) identified compound heterozygous mutations in the COG2 gene (606974.0001-606974.0002). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing; one mutation occurred de novo, whereas the other was inherited from the unaffected mother. 游侠点评：新发突变与另一遗传突变导致隐性遗传病 OMIM编号：617397 疾病：pseudo-TORCH 2型 表型：antenatal（产前） onset of intracranial hemorrhage（颅内出血）, calcification, brain malformations, liver dysfunction, and often thrombocytopenia（血小板减少症）. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy。 基因：USP18 背后的小故事：  In 3 sibs, born of consanguineous Turkish parents, with PTORCH2, Meuwissen et al. (2016) identified a homozygous truncating mutation in the USP18 gene (Q218X; 607057.0001). The mutation, which was found by a combination of linkage analysis, whole-exome sequencing, and capillary DNA sequencing, segregated with the disorder in the family. 游侠点评：近亲婚配导致的遗传病比较好分析致病基因 推送日期：2017.3.26 疾病：短肋胸廓发育不良17型 表型：skeletal ciliopathies that are characterized by a constricted thoracic cage（胸廓）, short ribs, shortened tubular（管状的） bones, and a 'trident' （三叉戟）appearance of the acetabular roof（髋臼顶）. 基因：TCTEX1D2 背后的小故事：  By whole-exome sequencing in 69 patients from 60 families clinically diagnosed with Jeune asphyxiating thoracic dysplasia, Schmidts et al. (2015) identified homozygosity for a splice site mutation in the TCTEX1D2 gene (617353.0001) in the proband from a consanguineous Turkish family (UCL82). Analysis of an additional 154 exomes from SRTD patients and Sanger sequencing of TCTEX1D2 in another 69 SRTD cases that previously had been excluded for mutations in known SRTD-associated genes revealed compound heterozygosity for a nonsense mutation (R88X; 617353.0002) and a deletion/insertion frameshift mutation (617353.0003) in the proband from a nonconsanguineous French family (INS). 游侠点评：先在近亲婚配找到候选致病基因，然后在散发病例中验证，get it。 本系列文章全部赞赏将捐给OMIM官方网站，目前已收到读者赞赏423元！ |
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