ADAMTS17 – Weill-Marchesani Syndrome 4 (Recessive)

ADAMTS17 is associated with autosomal recessive Weill-Marchesani 4 syndrome, recessive via biallelic loss-of-function and missense variants in extracellular matrix protease domains. Clinical hallmarks include microspherophakia, ectopia lentis, progressive myopia, secondary glaucoma, brachydactyly (HP:0001156), and short stature (HP:0004322), often without joint stiffness or cardiac defects. Early misdiagnosis as high myopia underscores the need for genetic evaluation in pediatric ocular anomalies.

Genetic evidence includes eight unrelated probands with compound heterozygous or homozygous ADAMTS17 variants across four studies ([PMID:36698805]; [PMID:35496767]; [PMID:31019231]; [PMID:37506754]). Variant spectrum comprises missense, nonsense, small in-frame deletions, and splice site variants. A representative allele is c.2254A>G (p.Ile752Val) identified in a child with progressive lens thickening and ocular hypertension ([PMID:36698805]).

Segregation analysis demonstrates autosomal recessive inheritance with co-segregation of variants in multiple families, including two affected siblings in a consanguineous pedigree ([PMID:31019231]) and complete co-segregation in a Newfoundland kindred ([PMID:32616716]). These data satisfy segregation criteria in three independent lineages.

Functional studies reveal impaired secretion and extracellular matrix deposition of ADAMTS17. A novel missense variant (p.Cys1023Tyr) showed significantly reduced secretion in HEK293T assays ([PMID:32616716]), while patient-derived fibroblasts with a spacer domain variant (p.Thr343Ala) exhibited intracellular accumulation of fibrillin-1 and collagen I and elastic fiber abnormalities ([PMID:31726086]). Together, these findings support a loss-of-function mechanism via disrupted ECM remodeling.

Comprehensive phenotyping reports lens subluxation (HP:0001132), shallow anterior chamber (HP:0000594), high myopia (HP:0011003), and progressive ocular hypertension (HP:0007906) in early childhood. Short stature and brachydactyly further distinguish WMS4 from other connective tissue disorders, guiding diagnostic surveillance and tailored surgical management for glaucoma and lens complications.

Early molecular diagnosis of ADAMTS17-related WMS4 enables proactive ophthalmic monitoring and timely surgical intervention to preserve vision and informs genetic counseling for at-risk families.

References

• Frontiers in Medicine • 2022 • Abnormal lens thickening in a child with Weill-Marchesani syndrome 4: A 3-year follow-up case report. PMID:36698805
• American Journal of Ophthalmology Case Reports • 2022 • Weill-Marchesani syndrome 4 caused by compound heterozygosity of a maternal submicroscopic deletion and a paternal nonsense variant in the ADAMTS17 gene: A case report. PMID:35496767
• Journal of Human Genetics • 2019 • A novel nonsense mutation in ADAMTS17 caused autosomal recessive inheritance Weill-Marchesani syndrome from a Chinese family. PMID:31019231
• Experimental Eye Research • 2023 • Characteristics and genotype-phenotype correlations in ADAMTS17 mutation-related Weill-Marchesani syndrome. PMID:37506754
• Scientific Reports • 2020 • A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features. PMID:32616716
• Matrix Biology • 2020 • A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix. PMID:31726086

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