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| Genomic newborn screening: ICoNS v0.39 | ALPL | Lilian Downie Marked gene: ALPL as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.39 | ALPL | Lilian Downie Gene: alpl has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.39 | ALPL | José Manuel González de Aledo Castillo reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.36 | ALPL |
Lilian Downie gene: ALPL was added gene: ALPL was added to Genomic newborn screening: ICoNS. Sources: Expert List Mode of inheritance for gene: ALPL was set to BIALLELIC, autosomal or pseudoautosomal Added comment: ClinGen ALPL is curated by the ClinGen Skeletal Disorders Gene Curation Expert Panel and has Definitive gene–disease validity for both ALPL-related autosomal recessive hypophosphatasia and ALPL-related autosomal dominant hypophosphatasia. Treatment Enzyme replacement therapy (ERT) for avoiding/reducing respiratory failure leading to long-term ventilatory support or death and for rickets or fractures, and also avoidance of bisphosphonates as a management consideration. Asfotase alfa (ERT) improves pulmonary function, bone health and calcium homeostasis, and survival in infantile and early childhood hypophosphatasia. Asfotase alfa improved survival in perinatal/infantile hypophosphatasia versus historical controls, with survival reported as 95% vs 42% at age 1 year and 84% vs 27% at age 5 years. Also marked benefit among treated patients needing respiratory support has been reported. Genomic newborn screening challenges The main genomic-screening challenge is the extreme phenotype spectrum: ALPL can cause perinatal lethal, infantile, childhood, adult, and odontohypophosphatasia presentations, and both AR and AD inheritance occur. Dominant-negative effects have been described in some autosomal dominant cases. Another major issue is reduced penetrance/variable expressivity, especially for heterozygous ALPL variants. Penetrance in adult heterozygotes is low or incompletely understood Variants of interest The ALPL field has created a dedicated international variant-classification project and database https://alplmutationdatabase.jku.at/ At the gene level, ALPL has more than 440 reported variants, including missense, nonsense, splice-site, small deletion/insertion, and other disruptive variants. Missense variants are common. Rather than a small number of recurrent variants, ALPL is characterized by broad allelic heterogeneity, with both loss-of-function and dominant-negative missense variants contributing to disease. Genomic newborn screening inclusion Included in most genomic newborn screening programs, but some of them just the recessive form Traditional newborn screening Hypophosphatasia is not part of standard routine traditional newborn screening panels. There is a pilot biochemical newborn screening study from Kumamoto Prefecture, Japan, which the authors describe as the first study on newborn screening for HPP worldwide. It used dried blood spots to measure TNAP (tissue-nonspecific alkaline phosphatase) activity in 45,632 newborns and identified one child who later showed HPP-related manifestations. Sources: Expert List |
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