ADAMTSL4 – Ectopia lentis et pupillae

ADAMTSL4 encodes an ADAMTS-like secreted glycoprotein essential for fibrillin microfibril biogenesis in the eye. Biallelic loss-of-function variants in ADAMTSL4 cause autosomal recessive ectopia lentis et pupillae (ELeP), characterized by lens subluxation, pupillary dysfunction, and axial elongation.

In a large Dutch pedigree, seven of eight affected individuals harbored homozygous nonsense (p.Gln752Ter) or compound heterozygous frameshift (c.2270dup (p.Gly758fs)) variants in ADAMTSL4, confirming AR inheritance by segregation in unaffected parents (PMID:23426735). A second family with three siblings exhibited compound heterozygous frameshift alleles (p.Ser264LeufsTer37/p.Gly757ValfsTer62) linked to ELeP over 12 years of follow-up (PMID:36089008). A pseudodominant pedigree described a 4-year-old proband and asymptomatic homozygous parent, highlighting variable expressivity despite a shared founder allele (PMID:35218299). In total, 11 unrelated probands across three families have been reported with biallelic ADAMTSL4 truncating variants.

Segregation analysis demonstrates complete concordance of biallelic LoF alleles with disease status; heterozygous carriers are asymptomatic, supporting a loss-of-function mechanism. No pathogenic missense or deep-intronic alleles have been recurrently reported.

Functional studies confirm ADAMTSL4 expression in human iris, ciliary body, and choroid but not neural retina, suggesting a role in zonule fiber anchorage (PMID:23846871). Adamtsl4 knockout mice recapitulate lens subluxation, pupillary defects, and increased axial length, mirroring human ELeP (PMID:26405179). In vitro mini-gene assays of the recurrent intronic variant c.2177+4A>G demonstrate exon-skipping, premature termination codons, and NMD, reducing ADAMTSL4 protein levels (PMID:39278391).

No conflicting reports have been published. The collective genetic and experimental data meet criteria for a Definitive gene–disease association: multiple pedigrees over >10 years, robust segregation, and concordant in vivo and in vitro functional evidence.

Key Take-home: Biallelic ADAMTSL4 loss-of-function variants reliably cause autosomal recessive Ectopia lentis et pupillae; genetic testing of ADAMTSL4 informs diagnosis, family counseling, and potential early ocular interventions.

References

• Experimental eye research • 2022 • Correlation between novel compound heterozygous ADAMTSL4 variants and primary phenotypes of ectopia lentis et pupillae. PMID:36089008
• American journal of medical genetics. Part A • 2022 • ADAMTSL4-related ectopia lentis: A case of pseudodominance with an asymptomatic parent. PMID:35218299
• The British journal of ophthalmology • 2013 • Ectopia lentis et pupillae in four generations caused by novel mutations in the ADAMTSL4 gene. PMID:23426735
• The British journal of ophthalmology • 2013 • Gene expression and protein distribution of ADAMTSL-4 in human iris, choroid and retina. PMID:23846871
• Human molecular genetics • 2015 • Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. PMID:26405179
• Experimental eye research • 2024 • Mutations in ADAMTSL4 cause a unique form of autosomal-recessive congenital ectopia lentis. PMID:39278391

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