{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T20:33:10Z","timestamp":1788294790437,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Acrocapitofemoral dysplasia (ACFD) is a rare autosomal recessive disorder, characterized by postnatal onset of disproportionate short stature with short limbs, brachydactyly, cone\u2010shaped epiphysis, narrow thorax, and relatively large head. To date, only three homozygous missense mutations have been reported in the signaling amino terminal domain (201\u2013308 amino acids) of the <jats:italic>IHH<\/jats:italic> gene in three ACFD families from Belgian, Dutch, and Turkish ethnicities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the present study, we have investigated two patients in a Pakistani family affected with ACFD. Whole exome sequencing (WES) followed by Sanger sequencing was carried out for mutational screening. The variant was further validated by in silico modeling and molecular dynamics simulation analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Data analysis revealed a novel homozygous missense variant [c.518C&gt;A; p.(Ala173Asp)] in exon 2 of the <jats:italic>IHH<\/jats:italic> (NM_002181.4) gene. The variant segregated within the family and was not observed in unaffected ethnically matched controls. In silico modeling and dynamic simulation analysis revealed that the variant disturbed the core structure of the domain and destabilized the loop region and the region surrounding the variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study reports the first case of ACFD from Pakistan and identifies the fourth novel missense variant in the <jats:italic>IHH<\/jats:italic> gene that led to the broadening of the phenotypic and genotypic spectrum of ACFD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70085","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T04:29:19Z","timestamp":1741753759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Novel Biallelic Variant in <scp><i>IHH<\/i><\/scp> Causing Acrocapitofemoral Dysplasia in a Pakistani 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