GENETIC CODES OF X-LINKED HYPOPHOSPHATEMIA

Year 2020, Volume: 83 Issue: S-1, 17 - 20, 13.05.2020

Hüseyin Onay

Abstract

X-linked hypophosphatemia (XLH, OMIM 307800) is the most common form of hereditary rickets and it is an X-linked dominantly inherited disorder. Loss of function mutations in the PHEX (Phosphate regulating gene with Homology to Endopeptidases on the X chromosome) gene are responsible for XLH. These mutations in the PHEX gene cause an elevation in FGF23 levels via an unknown mechanism. The first mutation in the PHEX gene was identified in 1955 and since then 467 different causal mutations have been identified. Mutations in the PHEX gene are distributed across all coding exons and exon-intron boundaries and there is no specific mutation hotspot in the gene. A genotype-phenotype correlation has not been well established. PHEX mutation screening is performed in a two-tier strategy. Sequencing of the coding exons and exon-intron boundaries can detect 85% of all causal mutations. Deletions/duplications are responsible for the remaining mutations and the MLPA (Multiple Ligation dependent Probe Amplification) method must be used in order to detect these mutations. Sibling/family screening is important in order to diagnose cases who have a high risk of developing XLH.

Keywords

X-linked hypophosphatemia, genetic diagnosis, mutation

X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI

Abstract

X’e bağlı hipofosfatemi (XLH, OMIM 307800) kalıtsal raşitizmin en sık gözlenen formudur ve X’e bağlı dominant bir kalıtım şekli gösterir. Hastalığın genetik temelini PHEX (Phosphate regulating gene with Homology to Endopeptidases on the X chromosome) genindeki fonksiyon kaybettirici mutasyonlar oluşturur. PHEX genindeki bu mutasyonlar, henüz bilinmeyen bir mekanizmayla FGF23’ün aşırı üretimine neden olur. Bu gendeki mutasyonlar X’e bağlı dominant olarak kalıtılır. PHEX genindeki ilk mutasyon 1955 yılında tanımlanmıştır ve o günden günümüze kadar hastalıkla ilgili toplam 467 farklı mutasyon bildirilmiştir. PHEX genindeki mutasyonlar gen boyunca dağınık olarak bulunurlar ve herhangibir mutasyon sıcak noktası bulunmamaktadır. XLH’de belirgin bir genotip-fenotip korelasyonu bulunmamaktadır. XLH’de PHEX mutasyon taraması iki basamaklı yapılmalıdır. Öncelikle dizi analizi yöntemi ile nokta mutasyonlar araştırılmalıdır. Tüm olguların yaklaşık %15’inde dizi analizi yöntemi ile saptanamayan büyük delesyon/duplikasyonlar bulunmaktadır ve bu mutasyonlar MLPA (Multiple Ligation dependent Probe Amplification) yöntemi ile taranmalıdır. Mutasyon saptanan olguların ailelerinde kardeş/aile taraması yapılması erken tanı için oldukça önemlidir.

Keywords

X’e bağlı hipofosfatemi, genetik tanı, mutasyon

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