13
Mar

1p31.3 Deletion Syndrome

Deletion 1p31.3

Location of 1p31.3 on Chromosome 1

The most known condition caused by deletion of the short arm of chromosome 1 is deletion 1p36. However, recent studies show that several more syndromes may be attributed to deletions of other segments of 1p. One of these conditions is deletion of the 1p31.3 segment. This segment includes the NFIA gene located at 60.865-61.463 Mb. NFIA is an important transcription factor whose main function is facilitating various differentiation pathways during embryogenesis1. It has been shown that those who have mutations or deletion in this gene, resulting in haploinsufficiency, causes a syndrome mainly characterized by central nervous system malformation, facial dysmorphisms, and urinary tract defects2,3.

At least 40 cases involving deletion of this area have been reported so far. Most cases of these deletions are reported to be de novo. However, the few cases that have been shown to be inherited from a parent are passed on in an autosomal dominant fashion4. Some deletions affect only NFIA gene whereas in other cases many other genes seem to be involved.

Most individuals with chromosomal deletion 1p31.3 have abnormalities in their central nervous system, intellectual disabilities, developmental delays, neuro-psychological problems, urinary tract defects, and some dysmorphic facial and bodily features.

Morphological defects of the brain and skull are the cornerstones of this condition. The most common defects are agenesis or hypoplasia of the corpus callosum which was found in 22 out of 38 informative cases. Craniosynostosis (premature closure of sutures between cranial bones) was reported in 13 cases (extremely high frequency compared to other chromosomal syndromes). Relatively frequent defects include macrocephaly (10) or hydrocephalus (4). Other defects include polymicrogyria, cerebellar defects, Chiari type I malformation or tethered spinal cord5. At least two patients had extremely rare Moyamoya disease – stenosis of arteries in the area of the basal ganglia.

Patients with 1p31.3 deletions also reveal intellectual disabilities, developmental delays, and behavior abnormalities. These disabilities and delays can range from mild to severe. Developmental delays can include delays in milestones such as crawling, sitting, walking, or other motor skills3. Neurological abnormalities can include bipolar disorder, depression, attention deficit hyperactivity disorder, obsessive compulsive disorder, and autism spectrum disorder4. Seizures have been reports at least in 5 patients.

Defects of the urinary system also are relatively common; they have been reported at least in 9 patients. These abnormalities include hydronephrosis, hypoplastic or ectopic kidneys. However most of these defects do not lead to renal insufficiency.

Defects of extremities are common but relatively mild (shortening of the limbs, proximally placed thumbs, camptodactyly etc.). Whereas dysmorphic facial features (high forehead, ptosis, low-set ears etc) are reported at least in 50% of patients.

All these defects are direct result of deletion of the NFIA gene because they present even in patients who did not lose any other genes.

 

References

1Bertini V, Cambi F, Valetto A. et al. (2022). Phenotypic spectrum of NFIA haploinsufficiency: two additional cases and review of the literature. Genes (Basel), v. 13 (12): 2249.

2Ji J, Salamon N, & Quintero-Rivera F. (2014). Microdeletion of 1p32-p31 involving NFIA in a patient with hypoplastic corpus callosum, ventriculomegaly, seizures and urinary tract defects. Europ J Med Genet v. 57 (6), 267-268.

3Labonne JD, Shen Y, Kim HG et al. (2016). Comparative deletion mapping at 1p31.3-p32.2 implies NFIA responsible for intellectual disability coupled with macrocephaly and the presence of several other genes for syndromic intellectual disability. Molec Cytogenetics v. 9:24.

4Colijn MA, Hrynchak M, Hrazdil CT et al. (2022). A 1p31.3 deletion encompassing the nuclear factor 1A gene presenting as possible temporal lobe epilepsy in association with schizoaffective disorder. Neurocase v. 28 (4): 382–387.

5Bayat A, Kirchhoff M, Kreiborg S et al. (2017). Familial craniofacial abnormality and polymicrogyria associated with a microdeletion affecting the NFIA gene. Clin Dysmorphology v. 26 (3): 148–153.

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