Autosomal Recessive Neurodevelopmental Disorder with Structural Brain Anomalies via the PTPN23 Gene

Biallelic pathogenic variants in the PTPN23 gene cause an autosomal recessive syndromic disorder of neurodevelopmental delay and structural brain anomalies with or without seizures and spasticity (NEDBASS). Shared characteristics of affected individuals include developmental delay (100%), brain abnormalities (mainly ventriculomegaly and/or brain atrophy)(90%), intellectual disability (100%), spasticity (80%), language disorder (80%), microcephaly (60%), optic atrophy (50%), and seizures (50%). Many affected individuals remain completely nonverbal throughout life. Death during childhood (infection related) occurs in about 25% of the cases identified thus far. Features observed more rarely include developmental regression, tremor, contractures, apraxia, spastic diplegia, corpus callosum dysgenesis, dysmyelination, cerebellar atrophy, congenital heart defects, and hypotonia. Dysmorphic features are observed, but variable, and there is no recognizable facial gestalt. Shared dysmorphic features included prominent forehead, strabismus, prominent low-set or posteriorly rotated ears, broad nasal bridge and nasal tip, and broad mouth with full lips (Bend et al. 2020. PubMed ID: 31395947).

PTPN23-associated syndrome is thought to be a very rare neurodevelopmental disorder, with less than 20 patients currently identified. While there are currently no treatments, patients and their families may benefit from a molecular diagnosis for prognostic information, early identification and treatment of symptoms (such as seizures), or for connecting with relevant family support groups. For family planning, prenatal testing or pre-implantation genetic diagnosis may be implemented for future pregnancies.

PTPN23-associated neurodevelopmental delay with stuctural brain anomalies is an autosomal recessive disorder. Variant types cover a broad range including missense, in-frame deletions, nonsense, and frameshift variants. However, no patients have an allele combination predicted to result in complete loss of function of PTPN23, and this is likely incompatible with life. Both homozygous and compound heterozygous causative variants have been observed. None of the observed or reported variants are recurrent, and no large deletions or duplications (CNVs) have been reported as causative, to our knowledge.

Regarding genotype-phenotype correlations, phenotype may be more severe in patients with one loss of function (nonsense, frameshift) variant in trans with a missense variant. Pathogenic variants are widely spread across the protein, but missense changes do cluster in one of the protein's four functional domains. Many of the pathogenic variants are observed at a low frequency in gnomAD, up to 0.06%, or ~160 heterozygous individuals and 0 homozygous individuals. Some pathogenic missense variants may be causative only when observed in trans with a protein-terminating variant, but not in the homozygous state (Bend et al. 2020. PubMed ID: 31395947). PTPN23 is relatively intolerant to loss of function variants (Genome Aggregation Database).

PTPN23 encodes a 1636 amino acid protein-tyrosine phosphatase, implicated in ciliogenesis, the endosomal sorting complex required for transport (ESCRT) pathway, and RNA splicing. It is located on chromosome 3p21.3, and is composed of 24 exons. It is essential for embryonic development in mice, with knockout mice showing significant abnormalities and embryonic lethality around E9 (Gingras et al. 2009. PubMed ID: 19378249).  PTPN23 has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Due to the rarity of this syndrome, the diagnostic yield of this test for individuals with syndromic intellectual disability or developmental delay is predicted to be very low (<0.1%). Diagnostic yield is expected to be higher if several of the other defining features - such as brain atrophy, microcephaly, optic atrophy, or spasticity are observed. Still, it is important to note the high clinical and genetic heterogeneity of intellectual disability, and improved diagnostic yields that result from testing large panels of genes as well as testing parents along with the patient using a trio approach. The analytical sensitivity of this test is expected to be high, as it will detect all types of PTPN23 pathogenic variants identified to date.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the PTPN23 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or 2x Sanger sequencing.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).