推送日期：2017.3.28

OMIM編號：270750

疾?。函d攣性截癱23型

表型：childhood-onset spastic paraplegia（痙攣性截癱） resulting in gait（步態(tài)） difficulties and associated with pigmentary（色素） abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions（病變）.

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.

游俠點評：該案例很好地詮釋了NGS的優(yōu)勢，如果朋友們之前有家系定位至某染色體區(qū)間而不確定基因的，現(xiàn)在就是最好的時機去定位致病基因

OMIM編號：617402

疾?。浩つw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.

游俠點評：看人家兩個小家系就發(fā)一篇AJHG，國內(nèi)的朋友們加油?。?/strong>

OMIM編號：617403

疾?。浩つw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.

游俠點評：又是一個之前文章未確定致病基因，后面繼續(xù)分析確定致病基因的案例

推送日期：2017.3.27

OMIM編號：617395

疾?。合忍煨蕴腔惓?q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（垂體） gland. Laboratory studies showed liver dysfunction, hypocupremia（低銅血癥）, and hypoceruloplasminemia（低銅藍蛋白血癥）, 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.

游俠點評：新發(fā)突變與另一遺傳突變導(dǎo)致隱性遺傳病

OMIM編號：617397

疾?。簆seudo-TORCH 2型

表型：antenatal（產(chǎn)前） onset of intracranial hemorrhage（顱內(nèi)出血）, calcification, brain malformations, liver dysfunction, and often thrombocytopenia（血小板減少癥）. 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.

游俠點評：近親婚配導(dǎo)致的遺傳病比較好分析致病基因

推送日期：2017.3.26

疾?。憾汤咝乩l(fā)育不良17型

表型：skeletal ciliopathies that are characterized by a constricted thoracic cage（胸廓）, short ribs, shortened tubular（管狀的） bones, and a 'trident' （三叉戟）appearance of the acetabular roof（髖臼頂）.

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).

游俠點評：先在近親婚配找到候選致病基因，然后在散發(fā)病例中驗證，get it。

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