ELP1 – Riley-Day syndrome

Familial dysautonomia (FD), or Riley-Day syndrome, is a rare autosomal recessive sensory and autonomic neuropathy caused by pathogenic variants in ELP1 (HGNC:5959) leading to a deficiency of the IκB kinase complex‐associated protein. Clinically, affected infants present in the neonatal period with episodic somnolence, failure to thrive, absent fungiform papillae, areflexia, labile blood pressure, and autonomic crises. Early molecular diagnosis informs prognosis, genetic counseling, and targeted therapy development.

Genetic evidence for a definitive gene–disease association includes the identification of biallelic ELP1 mutations in >15 unrelated FD patients (PMID:15797185, PMID:38764866, PMID:29147224, PMID:8599360, PMID:12687659), autosomal recessive segregation in 7 informative families (PMID:8599360), and a common founder intronic splice‐site mutation accounting for >99.5% of Ashkenazi Jewish FD chromosomes (PMID:12116234). A rarer missense allele, c.2086C>T (p.Arg696Trp), occurs in trans with the major splice defect in several patients (PMID:12577200).

The variant spectrum is led by the canonical splice-site change c.2204+6T>C, causing tissue-specific exon 20 skipping, with additional rare missense alleles and deep‐intronic changes reported in non‐Ashkenazi patients. The founder IVS20(+6T→C) mutation alone underlies >99.5% of FD cases in Ashkenazi Jewish families, supporting focused carrier and prenatal testing strategies.

Functional studies have characterized the molecular mechanism of pathogenicity as haploinsufficiency due to aberrant splicing. Quantitative RT‐PCR and protein assays demonstrate reduced wild-type IKBKAP transcript and IKAP protein in patient lymphoblasts, fibroblasts, and postmortem neural tissues (PMID:12577200). Small-molecule splicing modulators, including EGCG (PMID:14521957) and kinetin (PMID:17206408), increase exon 20 inclusion and restore IKAP expression in patient cells.

In vivo, a humanized IKBKAP transgenic mouse recapitulates the tissue-specific splicing defect (PMID:17644305), and the TgFD9;IkbkapΔ20/flox model replicates cardinal FD phenotypes including sensory and autonomic deficits (PMID:26769677). Therapeutic rescue has been demonstrated by kinetin-mediated splicing correction (PMID:30905397), splice-switching antisense oligonucleotides (PMID:29672717), and exon-specific U1 snRNAs (PMID:29701768).

Together, these genetic and functional data provide definitive evidence linking ELP1 to Riley-Day syndrome and underpin current strategies for carrier screening, prenatal diagnosis, and development of splice-modulating therapies. Key take-home: ELP1 testing and targeted splicing correction are clinically actionable for diagnosis, counseling, and precision therapy in familial dysautonomia.

References

• Pediatric neurology • 2005 • Episodic somnolence in an infant with Riley-Day syndrome. PMID:15797185
• Psychiatry and clinical psychopharmacology • 2022 • A Closer Look at Familial Dysautonomia from a Social Communication Perspective: A Case Report and Review of Literature. PMID:38764866
• World journal of oncology • 2011 • Increased Incidence of Tumors With the IKBKAP Gene Mutation? A Case Report and Review of the Literature. PMID:29147224
• American journal of medical genetics • 1995 • Prenatal diagnosis of familial dysautonomia by analysis of linked CA-repeat polymorphisms on chromosome 9q31-q33. PMID:8599360
• American journal of medical genetics • 2002 • Familial dysautonomia: detection of the IKBKAP IVS20(+6T → C) and R696P mutations and frequencies among Ashkenazi Jews. PMID:12116234
• American journal of human genetics • 2003 • Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. PMID:12577200
• Biochemical and biophysical research communications • 2003 • EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia. PMID:14521957
• Journal of molecular medicine • 2007 • Therapeutic potential and mechanism of kinetin as a treatment for the human splicing disease familial dysautonomia. PMID:17206408
• Genomics • 2007 • A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect. PMID:17644305
• Human molecular genetics • 2011 • Specific correction of a splice defect in brain by nutritional supplementation. PMID:21821670
• Human molecular genetics • 2016 • Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia. PMID:26769677
• Nucleic acids research • 2018 • Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice. PMID:29672717
• Human molecular genetics • 2018 • Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model. PMID:29701768
• American journal of human genetics • 2019 • ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia. PMID:30905397

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