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Pitt-Hopkins Syndrome via the TCF4 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
TCF4 81406 81406,81405 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8075TCF481406 81406,81405 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Li Fan, MD, PhD, FCCMG, FACMG

Clinical Features and Genetics

Clinical Features

Pitt-Hopkins syndrome is a rare disorder characterized by extensive developmental delay, severe intellectual disability, intermittent hyperventilation followed by apnea, tendency to epilepsy, absence of speech, stereotypic hand movements, postnatal microcephaly, ocular anomalies and distinctive facial dysmorphism (cupid’s bow mouth, fleshy lips, broad and beaked nasal bridge). To date, no major congenital malformations have been described. Onset of this disease occurs in infancy and childhood (Zweier et al 2007; Peippo and Ignatius 2012; Sweatt 2013). It has been suggested that this disorder may be underdiagnosed. Pitt-Hopkins syndrome overlaps with features from other disorders such as Rett syndrome, Angelman syndrome, Joubert syndrome, Mowat-Wilson syndrome, and ARX, NRXN1 or CNTNAP2 related intellectual disability disorders.


Pitt-Hopkins syndrome is inherited in an autosomal dominant manner and is caused by defects in the TCF4 gene encoding the transcription factor-4, a member of class I basic helix-loop-helix family. TCF4 is the only gene in which pathogenic variants are known to cause Pitt-Hopkins syndrome. The human TCF4 gene consists of 20 exons (exons 2 through 19 are coding exons) and spans 360 kb. It is transcribed into isoforms with 18 different N-terminals, as well as several isoforms with alternative splicing of internal exons (Sweatt 2013). The transcription factor-4 (TCF4) shares homology with several other basic helix-loop-helix transcription factors (Zweier et al. 2007). It is ubiquitously expressed during embryo development, particularly in the brain and retina. It is continuously expressed in adult brain and other organs (Sepp et al 2011). TCF4 forms a homodimer or heterodimers with other proteins, in order to bind DNA and regulate gene expression. Depending on the binding partner, TCF4 may be either a transcription activator or suppressor. Upstream and downstream effectors of the TCF4 signaling pathway are largely unknown (Sweatt 2013).

Haploinsufficiency of the TCF4 gene causes Pitt-Hopkins syndrome, while over-expression of the TCF4 gene in the brain is a risk factor to schizophrenia. Pathogenic variants in TCF4 gene include frameshift, nonsense, splice site, and missense, as well as large deletions. Most cases are caused by de novo pathogenic variants (Amiel et al. 2007; Zweier et al. 2007). The missense variants are generally within the basic helix-loop-helix domain, a hotspot for pathogenic variants (Sweatt 2013). DNA sequence analysis detects ~70% of TCF4 pathologic variants. However, ~30% of TCF4 pathologic variants are due to whole or partial gene deletions, which are generally not detectable by sequencing (Whalen et al. 2012).

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in TCF4 were confirmed by molecular analysis in 13 of 36 patients (~36%) who were either clinically diagnosed with Pitt-Hopkins syndrome (25 patients), or with Rett/Angelman syndrome, but had negative findings in MECP2 and UBE3A (10 patients), or with Mowat-Wilson syndrome, but had negative findings in ZFHX1B (de Pontual et al 2009).

Testing Strategy

This test provides full coverage of all coding exons of the TCF4 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

TCF4 gene sequencing test is recommended for patients who are suspected to have Pitt-Hopkins syndrome. Molecular genetic testing is the only confirmation for this disease. Candidates for TCF4 gene testing also include patients with suspected Rett syndrome, Angelman syndrome, Joubert syndrome, Mowat-Wilson syndrome, but have negative findings in genetic testing specifically for those syndromes. Prenatal diagnosis is possible if the genetic diagnosis has been established in an affected family member.


Official Gene Symbol OMIM ID
TCF4 602272
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Pitt-Hopkins Syndrome AD 610954


  • Amiel J. et al. 2007. American journal of human genetics. 80: 988-93. PubMed ID: 17436254
  • de Pontual L. et al. 2009. Human mutation. 30: 669-76. PubMed ID: 19235238
  • Peippo M., Ignatius J. 2012. Molecular syndromology. 2: 171-180. PubMed ID: 22670138
  • Sepp M. et al. 2011. PloS one. 6: e22138. PubMed ID: 21789225
  • Sweatt J David. 2013. Experimental & Molecular Medicine. 45: e21 PubMed ID: 23640545
  • Whalen S. et al. 2012. Human mutation. 33: 64-72. PubMed ID: 22045651
  • Zweier C. et al. 2007. American journal of human genetics. 80: 994-1001. PubMed ID: 17436255


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

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2) Select Additional Test Options

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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