Rare Variants in the Gene ALPL That Cause Hypophosphatasia Are Strongly Associated With Ovarian and Uterine Disorders

Dahir, Kathryn; Tilden, Daniel R.; Warner, Jeremy L.; Bastarache, Lisa; Gifford, Aliya; Ramirez, Andrea H.; Simmons, Jill H.; Black, Margo; Newman, John H.; Denny, Josh C.

doi:10.1210/jc.2017-02676

Cited by 7 publications

(6 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One reason for this could be that the indicated reference range may not take sufficient account of age and gender variations. In patients with pathogenic ALPL variants that were identified by a genetic screening study of unselected patients, more than 40 percent had TNSALP levels above the reference range 40 U/l [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

et al. 2020

View full text Add to dashboard Cite

Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5′-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

et al. 2020

View full text Add to dashboard Cite

show abstract

“…variant, ~50% of heterozygotes for an ALPL variant [24/52 [43], and 53/105 [20]] express a phenotype. The patients reported carried m or s alleles only [20], or mostly m or s alleles [43].…”

Section: Mild Hpps Is Expected To Be Very Common In the European Popu...mentioning

confidence: 99%

“…Indeed, imaging, clinical, and biological investigations are limited in prenatal context so that differential diagnoses may be difficult to exclude, especially OI. In adult HPP, when symptoms are nonspecific, the disease is difficult to prove even when AP is low, which has been reported in an increasing number of common pathologies including osteoporosis, arthropathies, chondrocalcinosis [19], and more recently ovarian and uterine disorders [20]. Genetic confirmation of the diagnosis is therefore very useful.…”

Section: Introductionmentioning

confidence: 99%

Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation

et al. 2020

View full text Add to dashboard Cite

Hypophosphatasia (HPP) is caused by pathogenic variants in the ALPL gene. There is a large continuum in the severity, ranging from a lethal perinatal form to dental issues. We analyzed a cohort of 424 HPP patients from European geographic origin or ancestry. Using 3D modeling and results of functional tests we classified ALPL pathogenic variants according to their dominant negative effect (DNE) and their severity. The cohort was described by the genotypes resulting from alleles s (severe recessive), Sd (severe dominant), and m (moderate). Many recurrent variants showed a regional anchor pointing out founder effects rather than multiple mutational events. Homozygosity was an aggravating factor of the severity and moderate alleles were rare both in number and frequency. Pathogenic variants with DNE were found in both recessive and dominant HPP. Sixty percent of the adults tested were heterozygous for a variant showing no DNE, suggesting another mechanism of dominance like haploinsufficiency. Adults with dominant HPP without DNE were found statistically less severely affected than adults with DNE variants. Adults with dominant HPP without DNE represent a new clinical entity mostly diagnosed from 2010s, characterized by nonspecific signs of HPP and low alkaline phosphatase, and for which a high prevalence is expected. In conclusion, the genetic composition of our cohort suggests a nosology with 3 clinical forms: severe HPP is recessive and rare, moderate HPP is recessive or dominant and more common, and mild HPP, characterized by low alkaline phosphatase and unspecific clinical signs, is dominantly inherited and very common.

show abstract

“…Accordingly, ALPL variants that were previously considered benign have now been linked to HPP with milder phenotypes or with lower penetrance. A sequential genome-wide association study indicated that ALPL variants are also more prevalent than previously estimated [18], and the variant c.787T>C appears to be a representative example of this situation.…”

Section: Discussionmentioning

confidence: 92%

“…The recent better understanding of HPP pathogenesis and manifestations has enabled the clearer recognition of subtle clinical phenotypes [18,19]. This has been accompanied by an increased rate of HPP diagnosis, including those of milder phenotypes, suggesting a higher incidence than previously estimated.…”

Section: Discussionmentioning

confidence: 99%

Potential pathological role of single nucleotide polymorphism (c.787T>C) in <i>alkaline phosphatase (ALPL)</i> for the phenotypes of hypophosphatasia

et al. 2020

View full text Add to dashboard Cite

Hypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is an inherited metabolic disease characterized by defects of bone and tooth mineralization, which is caused by loss-of-function mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP). In the last three decades, several studies have focused on the genotypephenotype correlation in hypophosphatasia (HPP). In particular, functional tests based on in vitro analysis for the residual enzymatic activities of mutations have revealed a clear but imperfect genotype-phenotype correlation, suggesting that multiple potential factors modulate the phenotype. One of the missense variants identified in the tissue non-specific alkaline phosphatase (ALPL) gene, c.787T>C, has been considered as a benign polymorphism in HPP; however, its pathogenicity and role in disease manifestation remain controversial. We here report our recent experience of three unrelated families harboring the c.787T>C variant, suggesting clinical implications regarding the controversial pathogenicity of c.787T>C. First, despite the lack of obvious clinical phenotypes, homozygous c.787T>C would decrease the serum level of ALP activity. Second, c.787T>C might deteriorate phenotypes of a patient harboring another ALPL variant, especially one that has thus far presumed to be benign, e.g., the c.1144G>A variant. These cases contribute to the recent advances in understanding HPP to facilitate clinical recognition of more subtle phenotypes, further providing insights into the pathogenesis of HPP.

show abstract

Rare Variants in the Gene ALPL That Cause Hypophosphatasia Are Strongly Associated With Ovarian and Uterine Disorders

Abstract: Variants in the ALPL gene cause bone and dental disease in patients with and without the standard biomarker, low plasma AlkP. ALPL gene variants are more prevalent than currently reported and underdiagnosed. Gynecologic disease appears to be associated with HPP-causing variants in ALPL.

Cited by 7 publications

References 32 publications

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation

Potential pathological role of single nucleotide polymorphism (c.787T>C) in <i>alkaline phosphatase (ALPL)</i> for the phenotypes of hypophosphatasia

Contact Info

Product

Resources

About