Submission Details

HNRNPD encodes a nuclear ribonucleoprotein implicated in mRNA processing mechanisms. HNRNPD was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2021 (Gillentine et al., PMID: 33874999). Reported phenotypes include developmental delay, intellectual disability, speech and language delay, autism spectrum disorder, brain imaging abnormalities, growth delay, hypotonia, seizures, dystonia, dysmorphic facial features, and hand and feet abnormalities. Additional case reports with detailed clinical information are needed to better understand the phenotype spectrum.

Fourteen variants (frameshift, nonsense, splice, and single gene deletion) that have been reported in 17 probands in four publications (PMIDs: 24768552, 33057194, 33874999, 35982159) are included in this curation. Fourteen occurred de novo and four were of unknown inheritance. HNRNPD is significantly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.22, gnomAD v4.1.0). The fact that the majority of the reported variants are nonsense, frameshift or splice variants is consistent with a loss-of-function mechanism, but no functional studies have been performed.

This gene-disease relationship is also supported by biochemical function and protein interaction. HNRNPD belongs to the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family; several genes of this family (HNRNPC, HNRNPH1, HNRNPH2, HNRNPK, SYNCRIP [also known as HNRNPQ], HNRNPR, and HNRNPU) have been recently implicated in neurodevelopmental disorders with overlapping clinical features, including developmental delay, intellectual disability, autism spectrum disorder, epilepsy, and congenital anomalies.

In summary, there is definitive evidence supporting the relationship between HNRNPD and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 17, 2025 (SOP Version 11).

HNRNPD encodes a nuclear ribonucleoprotein implicated in mRNA processing mechanisms. HNRNPD was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2021 (Gillentine et al., PMID: 33874999). Reported phenotypes include developmental delay, intellectual disability, speech and language delay, autism spectrum disorder, brain imaging abnormalities, growth delay, hypotonia, seizures, dystonia, dysmorphic facial features, and hand and feet abnormalities. Additional case reports with detailed clinical information are needed to better understand the phenotype spectrum.

Fourteen variants (frameshift, nonsense, splice, and single gene deletion) that have been reported in 17 probands in four publications (PMIDs: 24768552, 33057194, 33874999, 35982159) are included in this curation. Thirteen occurred de novo and four were of unknown inheritance. HNRNPD is significantly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.22, gnomAD v4.1.0). The fact that the majority of the reported variants are nonsense, frameshift or splice variants is consistent with a loss-of-function mechanism, but no functional studies have been performed.

This gene-disease relationship is also supported by biochemical function and protein interaction. HNRNPD belongs to the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family; several genes in this family (HNRNPC, HNRNPH1, HNRNPH2, HNRNPK, SYNCRIP [also known as HNRNPQ], HNRNPR, and HNRNPU) have recently been implicated in neurodevelopmental disorders with overlapping clinical features, including developmental delay, intellectual disability, autism spectrum disorder, epilepsy, and congenital anomalies.

In summary, there is definitive evidence supporting the relationship between HNRNPD and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 17, 2025 (SOP Version 11).