DNA strand with scales representing ichthyosis prematurity syndrome and novel FATP4 mutations.

Ichthyosis Prematurity Syndrome: Unraveling the Genetic Mysteries

Jordan Keane in Health & Wellness December 2025 • 4 min read.

"A Deep Dive into Novel FATP4 Mutations and Their Impact on Spanish Sisters"

Ichthyosis prematurity syndrome (IPS), also known as ichthyosis congenita type IV, is a rare genetic condition characterized by abnormalities in the skin. This condition arises from mutations affecting the FATP4 gene, which plays a crucial role in fatty acid transport. When the FATP4 gene is disrupted, individuals typically exhibit premature birth coupled with distinctive skin features, including thick desquamation. Additional complications may include neonatal asphyxia, eosinophilia, and elevated levels of serum immunoglobulin E. Over time, symptoms may lessen in severity, transitioning into non-scaly ichthyosis accompanied by follicular hyperkeratosis during adulthood.

In a recent case study, two sisters born to non-consanguineous parents sought genetic counseling, presenting with notable symptoms. These included dark scales on their scalps, trunks, and limbs, without the presence of palmoplantar keratoderma, alopecia, or erythroderma. Initial genetic testing ruled out autosomal recessive congenital ichthyosis-related genes, prompting further investigation into their condition.

This article delves into the groundbreaking discovery of novel compound heterozygous FATP4 mutations identified in these Spanish sisters, providing new insights into the genetic underpinnings of ichthyosis prematurity syndrome. By unraveling the specific mutations and their functional consequences, this research opens avenues for improved diagnostics, potential therapeutic strategies, and a deeper understanding of this rare and complex genetic disorder.

Decoding the FATP4 Mutations: A Genetic Investigation

DNA strand with scales representing ichthyosis prematurity syndrome and novel FATP4 mutations.

The genetic analysis began with extracting DNA and RNA from blood samples of the patients, their parents, and a control group of nine healthy individuals. This meticulous approach allowed researchers to compare the genetic makeup of affected individuals with that of healthy controls, pinpointing the specific mutations responsible for the condition.

Sequence analysis of the FATP4 gene revealed two heterozygous variants in each patient. The first was a frameshift mutation, c.1322dup; p.(Gly442Argfs2), and the second an intronic variant, c.988-19A>G. The intronic variant had been previously reported in the gnomAD database (rs746178942), but its functional significance remained unclear. Researchers decided to investigate this variant at the RNA level, prompted by several factors: both patients and their mother were heterozygous carriers, the variant was absent in a control group, and preliminary predictions suggested it could alter splicing.

Frameshift Mutation (c.1322dup): This type of mutation disrupts the normal reading frame of the gene, leading to a premature stop codon and a truncated protein.
Intronic Variant (c.988-19A>G): Located in a non-coding region of the gene, this variant was suspected of affecting RNA splicing, a crucial step in gene expression.

RT-PCR analysis revealed a unique aberrant transcript, an in-frame ∆8p, in both patients and their mother. This transcript was missing the first 45 base pairs of exon 8, which encodes the last residues of the ATP/AMP domain. Computational analysis predicted that the intronic variant could indeed alter an intronic splicing enhancer site, affecting how the gene is processed into functional RNA.

New Avenues for Understanding and Treating Ichthyosis

This research presents, for the first time, the genetic characterization of two Spanish patients with IPS and novel FATP4 mutations. It also helps clarify the mechanism by which the c.988-19A>G variant may act and contribute to a better understanding of FATP4 splicing events. While IPS mainly occurs in Scandinavia, this case highlights that patients of various ethnicities have been reported (1,2), though not previously in Spain.

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Everything You Need To Know

What is Ichthyosis Prematurity Syndrome, and what does it entail?

Ichthyosis Prematurity Syndrome (IPS), also known as ichthyosis congenita type IV, is a rare genetic condition. It is characterized by skin abnormalities resulting from mutations in the FATP4 gene. This syndrome's significance lies in its implications for skin development and overall health. Individuals with IPS often experience premature birth and exhibit distinctive skin features, such as thick desquamation. It can also lead to other complications, including neonatal asphyxia, eosinophilia, and elevated levels of serum immunoglobulin E. In adulthood, the severity of symptoms may lessen, evolving into non-scaly ichthyosis and follicular hyperkeratosis.

What is the role of the FATP4 gene, and why is it important?

The FATP4 gene is crucial for fatty acid transport within the body. When this gene is disrupted by mutations, it leads to the development of Ichthyosis Prematurity Syndrome (IPS). The importance of the FATP4 gene stems from its role in maintaining healthy skin. Disruptions to this gene impair the skin's normal processes, leading to the characteristic symptoms of IPS. This includes the development of dark scales, and other skin related complications as discussed in the context.

What is the frameshift mutation, and what are its implications?

The frameshift mutation (c.1322dup) alters the reading frame of the FATP4 gene, causing a premature stop codon. This results in a truncated and likely non-functional protein. In the context of Ichthyosis Prematurity Syndrome (IPS), this mutation prevents the proper transport of fatty acids, which are essential for healthy skin. The implications are the characteristic skin abnormalities, such as thick desquamation and the potential for other health complications. The intronic variant (c.988-19A>G) affects RNA splicing, which is a key step in gene expression, resulting in aberrant transcripts and in-frame ∆8p.

What does the intronic variant do, and why is it important?

The intronic variant c.988-19A>G is located in a non-coding region of the FATP4 gene and was found to affect RNA splicing. This variant was suspected of altering an intronic splicing enhancer site, which is important for the correct processing of RNA. The impact of this variant is that it can lead to the production of abnormal transcripts, affecting the function of the FATP4 gene. This understanding of how the variant works gives insights into the genetic underpinnings of Ichthyosis Prematurity Syndrome (IPS) and potential targets for therapeutic intervention. Through RT-PCR analysis a unique aberrant transcript, an in-frame ∆8p, was found in the patients and their mother.

What was the process of genetic analysis, and what was the significance of the findings?

The genetic analysis involved extracting DNA and RNA samples from patients, their parents, and a control group. This process allowed researchers to identify novel compound heterozygous FATP4 mutations in the Spanish sisters. The significance of this analysis lies in the identification of specific mutations, which provides insights into the genetic basis of Ichthyosis Prematurity Syndrome (IPS). Moreover, the investigation of how the intronic variant affected RNA splicing allows a better understanding of the FATP4 splicing events. The case study helps to improve diagnostics and research and paves the way for potential therapeutic strategies for this rare genetic disorder.