A 6-Year-Old Male Presenting with X-Linked Intellectual Development Disorder Due to a Unique Pathogenic Truncating Variant in IL1RAPL1
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
The Interleukin 1 Receptor Accessory Protein-Like 1, IL1RAPL1 (OMIM #300206), has 11 exons spanning across the Xp21.3-21.2 region. The protein product is localized to the postsynaptic compartment of excitatory synapses and plays a critical role in dendritic development through its interaction with neuronal calcium sensors (NCS). Patients with pathogenic variants in IL1RAPL1 present with Intellectual Developmental Disorder, X-linked 21 (IDD21; OMIM #300143). Most reported patients are male; however, some cases suggest variable phenotypic penetrance in heterozygous mothers. Existing literature is yet to define a direct ligand of IL1RAPL1, while the protein targets that it interacts with downstream are much more well defined. One of the most notable of these proteins, NCS1, plays a crucial role in allowing for calcium influx, ultimately contributing to the establishment of Long-Term Potentiation. Functional inactivation of this gene has been characterized by developmental and intellectual disability, autism, facial dysmorphisms, and behavioral problems. Limited literature has been published regarding IDD21, and of these cases, the molecular causes are highly variable; with abnormalities arising most commonly through deletions in portions of Xp21, but also occurring through premature truncation, mRNA fusion events, and more rarely, missense variants induced by single-nucleotide substitutions.
Case Presentation
We present the case of an affected male with a nonsense variant, specifically c.148C>T;p.R50*, in IL1RAPL1. This male was born to a 21-year-old, primigravid mother by emergency C-section due to excessive bleeding. Prenatal exposures included alcohol, marijuana, and nicotine. The neonatal course was complicated by failure to thrive and parental neglect. He was evaluated at 6 years of age with global delays, autism spectrum disorder, intellectual disability, aggression (including self-injury), astigmatism, hypotonia, brachycephaly, resolving plagiocephaly with a prominent forehead and round face, pes planus, frequent gagging incidents, episodic leg paints, and hyperlipidemia. This patient scored an IQ of 48 on the Wechsler Intelligence Scale at age 5. At the time of most recent encounter, this patient was in the 73rd, >99th, and >99th percentile for height, weight, and head circumference, respectively for their age. Family history was notable for intellectual disability in a maternal uncle.
Diagnostic Workup
Whole exome sequencing revealed a hemizygous pathogenic variant c.148C>T;p.R50* in IL1RAPL1. Also, a chromosomal microarray preformed 1 year prior revealed a 396kbp mosaic duplication of 12p13.31 (variant of unknown significance). Neither the intellectually disabled maternal uncle, nor either of his biological parents, partook in the genetic workup.
Treatment and Management
Behavioral concerns and observation of developmental delays prompted the suggestion of further consultation with occupational therapy, physical therapy, and continued Special Education with the goal being to maximize long term developmental potential.
Outcome and Follow-Up
At two months post diagnosis, patient is still displaying aggressive symptoms, especially at home. No other notes at this time as diagnosis was recent.
Discussion
This patient displays many characteristics that are consistent with those possessing full deletions of the gene, as well as some novel features. It is important to note that his mosaic 12p copy number variant is of unknown significance and therefore is not considered to be a factor in his adverse phenotypes at this time. While it was not possible to document origin of the variant, it is consistent with the family history as provided. It is known that this patient was exposed to several teratogens throughout the course of fetal development; however, alcohol, nicotine, and cannabis use in pregnancy is less likely than genetic factors to explain the adverse phenotypes observed in this patient.
Conclusion
This case extends the literature on Intellectual Developmental Disorder, X-linked 21, in a patient who presents with a unique nucleotide substitution resulting in a stop-gain, one of the more rarely documented causes of IDD21.
The Interleukin 1 Receptor Accessory Protein-Like 1, IL1RAPL1 (OMIM #300206), has 11 exons spanning across the Xp21.3-21.2 region. The protein product is localized to the postsynaptic compartment of excitatory synapses and plays a critical role in dendritic development through its interaction with neuronal calcium sensors (NCS). Patients with pathogenic variants in IL1RAPL1 present with Intellectual Developmental Disorder, X-linked 21 (IDD21; OMIM #300143). Most reported patients are male; however, some cases suggest variable phenotypic penetrance in heterozygous mothers. Existing literature is yet to define a direct ligand of IL1RAPL1, while the protein targets that it interacts with downstream are much more well defined. One of the most notable of these proteins, NCS1, plays a crucial role in allowing for calcium influx, ultimately contributing to the establishment of Long-Term Potentiation. Functional inactivation of this gene has been characterized by developmental and intellectual disability, autism, facial dysmorphisms, and behavioral problems. Limited literature has been published regarding IDD21, and of these cases, the molecular causes are highly variable; with abnormalities arising most commonly through deletions in portions of Xp21, but also occurring through premature truncation, mRNA fusion events, and more rarely, missense variants induced by single-nucleotide substitutions.
Case Presentation
We present the case of an affected male with a nonsense variant, specifically c.148C>T;p.R50*, in IL1RAPL1. This male was born to a 21-year-old, primigravid mother by emergency C-section due to excessive bleeding. Prenatal exposures included alcohol, marijuana, and nicotine. The neonatal course was complicated by failure to thrive and parental neglect. He was evaluated at 6 years of age with global delays, autism spectrum disorder, intellectual disability, aggression (including self-injury), astigmatism, hypotonia, brachycephaly, resolving plagiocephaly with a prominent forehead and round face, pes planus, frequent gagging incidents, episodic leg paints, and hyperlipidemia. This patient scored an IQ of 48 on the Wechsler Intelligence Scale at age 5. At the time of most recent encounter, this patient was in the 73rd, >99th, and >99th percentile for height, weight, and head circumference, respectively for their age. Family history was notable for intellectual disability in a maternal uncle.
Diagnostic Workup
Whole exome sequencing revealed a hemizygous pathogenic variant c.148C>T;p.R50* in IL1RAPL1. Also, a chromosomal microarray preformed 1 year prior revealed a 396kbp mosaic duplication of 12p13.31 (variant of unknown significance). Neither the intellectually disabled maternal uncle, nor either of his biological parents, partook in the genetic workup.
Treatment and Management
Behavioral concerns and observation of developmental delays prompted the suggestion of further consultation with occupational therapy, physical therapy, and continued Special Education with the goal being to maximize long term developmental potential.
Outcome and Follow-Up
At two months post diagnosis, patient is still displaying aggressive symptoms, especially at home. No other notes at this time as diagnosis was recent.
Discussion
This patient displays many characteristics that are consistent with those possessing full deletions of the gene, as well as some novel features. It is important to note that his mosaic 12p copy number variant is of unknown significance and therefore is not considered to be a factor in his adverse phenotypes at this time. While it was not possible to document origin of the variant, it is consistent with the family history as provided. It is known that this patient was exposed to several teratogens throughout the course of fetal development; however, alcohol, nicotine, and cannabis use in pregnancy is less likely than genetic factors to explain the adverse phenotypes observed in this patient.
Conclusion
This case extends the literature on Intellectual Developmental Disorder, X-linked 21, in a patient who presents with a unique nucleotide substitution resulting in a stop-gain, one of the more rarely documented causes of IDD21.