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Purpose <p>The <i>ERBB4</i> gene encodes a tyrosine kinase receptor for neuregulins and EGF family members, and plays a crucial role in various neurobiological processes. At present, the phenotypic manifestations of genetic variants that disrupt <i>ERBB4</i> gene function (null variants) are not well established.</p> Methods <p>A search for new patients with null variants in <i>ERBB4</i> was initiated through an international data-sharing collaboration via GeneMatcher, and by searching the databases Decipher and ClinVar. Diagnosis had been performed using chromosomal microarray analysis, whole-exome sequencing, or whole-genome sequencing.</p> Results <p>Twenty-four new patients from 13 unrelated families with null variants in <i>ERBB4</i> were identified. Genetic findings included single- or multiple-exon deletions in eight families, a reciprocal translocation disrupting <i>ERBB4</i> in one family, and sequence variants in four. Variants arose de novo in four probands, were inherited in eight, and had an unknown inheritance pattern in one. Co-segregation of variants with clinical manifestations was observed within families. The predominant clinical features included neurodevelopmental disorders (intellectual disability, neurodevelopmental delay, autism spectrum disorder, and attention deficit hyperactivity disorder), speech delay, challenging behaviors, hypotonia, psychiatric conditions and seizures.</p> Conclusion <p>This study represents the largest case series of patients with neurological disorders and null variants in the <i>ERBB4</i> gene. Our findings support haploinsufficiency as the most plausible pathophysiological mechanism underlying <i>ERBB4</i>-related disorders and broaden the spectrum of associated phenotypes. Autism spectrum disorders and psychiatric manifestations have emerged as frequent, previously underrecognized features. Penetrance appears to be high but incomplete, and expressivity is highly variable, with a tendency toward intrafamilial phenotypic conservation.</p>

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Insight into Haploinsufficiency of the ERBB4 Gene: Expanding the Spectrum of Associated Phenotypes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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  • Irene Mademont-Soler,
  • Maria Camós-Carreras,
  • Aurore Garde,
  • A. Micheil Innes,
  • Dijana Perovic,
  • Barbara Golob,
  • Aida Palacín,
  • Henry Joel Mroczkowski,
  • Kameryn M. Butler,
  • Paulien Van Galen,
  • Gabriela Oprea,
  • Özge Güngör,
  • Dolors Casellas-Vidal,
  • Gemma Hernández,
  • Himanshu Goel,
  • Julia Appleby,
  • Ruzica Kravljanac,
  • Kenya De Leon,
  • Aboulfazl Rad,
  • Merve Yavuz,
  • Najim Ameziane,
  • Asude Durmaz,
  • Cristina Popescu,
  • Ayça Aykut,
  • Haluk Akın,
  • Figen Gökçay,
  • Ioana Mindruta,
  • Brankica Bosankic,
  • Renee Perrier,
  • William Burns,
  • Debra L. Hanna,
  • Nela Maksimovic,
  • Borut Peterlin,
  • Bradley Prince,
  • Hana Safraou,
  • Maria Obón,
  • Susanna Esteba-Castillo

摘要

Purpose

The ERBB4 gene encodes a tyrosine kinase receptor for neuregulins and EGF family members, and plays a crucial role in various neurobiological processes. At present, the phenotypic manifestations of genetic variants that disrupt ERBB4 gene function (null variants) are not well established.

Methods

A search for new patients with null variants in ERBB4 was initiated through an international data-sharing collaboration via GeneMatcher, and by searching the databases Decipher and ClinVar. Diagnosis had been performed using chromosomal microarray analysis, whole-exome sequencing, or whole-genome sequencing.

Results

Twenty-four new patients from 13 unrelated families with null variants in ERBB4 were identified. Genetic findings included single- or multiple-exon deletions in eight families, a reciprocal translocation disrupting ERBB4 in one family, and sequence variants in four. Variants arose de novo in four probands, were inherited in eight, and had an unknown inheritance pattern in one. Co-segregation of variants with clinical manifestations was observed within families. The predominant clinical features included neurodevelopmental disorders (intellectual disability, neurodevelopmental delay, autism spectrum disorder, and attention deficit hyperactivity disorder), speech delay, challenging behaviors, hypotonia, psychiatric conditions and seizures.

Conclusion

This study represents the largest case series of patients with neurological disorders and null variants in the ERBB4 gene. Our findings support haploinsufficiency as the most plausible pathophysiological mechanism underlying ERBB4-related disorders and broaden the spectrum of associated phenotypes. Autism spectrum disorders and psychiatric manifestations have emerged as frequent, previously underrecognized features. Penetrance appears to be high but incomplete, and expressivity is highly variable, with a tendency toward intrafamilial phenotypic conservation.