Spectrum of Congenital Anomalies in Myhre Syndrome—Insights Into Effects Brought by Altered <scp>TGF</scp> ‐β Signaling via Gain‐of‐Function Variants in <scp> <i>SMAD4</i> </scp>

Myhre syndrome is a rare genetic disorder characterized by progressive multisystem involvement. Gain-of-function missense heterozygous variants affecting the Ile500 residue and Arg496 residue of the SMAD4 gene are implicated in this condition. In this article, we aim to understand the spectrum of congenital anomalies in Myhre syndrome by studying a cohort of previously unreported patients alongside published literature. Our analysis revealed that the musculoskeletal system was the most common system to be affected, followed by the cardiovascular system. Intrauterine growth restriction was the most reported intrauterine anomaly. Although there was no clear genotype-phenotype correlation, it appears that the Ile500Thr variant showed early multisystem involvement compared to other variants.

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Publication Details

Journal
American Journal of Medical Genetics Part C Seminars in Medical Genetics
Published
2026-04-13
DOI
https://doi.org/10.1002/ajmg.c.70007
Primary Topic
Connective tissue disorders research
Type
article
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article

Spectrum of Congenital Anomalies in Myhre Syndrome—Insights Into Effects Brought by Altered TGF ‐β Signaling via Gain‐of‐Function Variants in SMAD4

Kawmadi Gunawardena, Emma Kivuva, Usha Kini, Tazeen Ashraf et al.
American Journal of Medical Genetics Part C Seminars in Medical Genetics
Connective tissue disorders research
article

Spectrum of Congenital Anomalies in Myhre Syndrome—Insights Into Effects Brought by Altered TGF ‐β Signaling via Gain‐of‐Function Variants in SMAD4

Kawmadi Gunawardena, Emma Kivuva, Usha Kini, Tazeen Ashraf, Shane McKee, Erina Sasaki, Nicola Brunetti‐Pierri, Deborah Osio, Nayana Lahiri, Alessandro De Falco, Francis H. Sansbury, Sahar Mansour, Eleanor Sherlock
article en

Abstract

Myhre syndrome is a rare genetic disorder characterized by progressive multisystem involvement. Gain-of-function missense heterozygous variants affecting the Ile500 residue and Arg496 residue of the SMAD4 gene are implicated in this condition. In this article, we aim to understand the spectrum of congenital anomalies in Myhre syndrome by studying a cohort of previously unreported patients alongside published literature. Our analysis revealed that the musculoskeletal system was the most common system to be affected, followed by the cardiovascular system. Intrauterine growth restriction was the most reported intrauterine anomaly. Although there was no clear genotype-phenotype correlation, it appears that the Ile500Thr variant showed early multisystem involvement compared to other variants.

American Journal of Medical Genetics Part C Seminars in Medical Genetics
Cardiff and Vale University Health Board (GB), University of Ulster (GB), Royal Devon & Exeter NHS Foundation Trust (GB), Great Ormond Street Hospital (GB), St George’s University Hospitals NHS Foundation Trust (GB), Belfast City Hospital (GB), University of Oxford (GB), Oxford University Hospitals NHS Trust (GB), Scuola Superiore Meridionale (IT), Telethon Institute Of Genetics And Medicine (IT), Birmingham Women’s and Children’s NHS Foundation Trust (GB), University College London (GB), University of Naples Federico II (IT), Cardiff University (GB)
Openalex Percentile: Top 16%
Connective tissue disorders research
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