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Reposted by Aaron Besterman

The Transmitter @thetransmitter.bsky.social · 5d

The awarded projects plan to study gene-and-environment interactions in people, stem cells and organoids, as well as predictors of positive life outcomes in autistic youth and adults.

By @callimcflurry.bsky.social

www.thetransmitter.org/spectrum/mee...

Meet the Autism Data Science Initiative grantees

The projects plan to study gene-and-environment interactions in people, stem cells and organoids, as well as predictors of positive life outcomes.

www.thetransmitter.org

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Aaron Besterman @abesterman.bsky.social · 5d

@biologicalpsych.bsky.social @ispg.bsky.social

Aaron Besterman @abesterman.bsky.social · 5d

11/ Gratitude to an amazing collaborative team led by Harman Brah. @bogglerapture.bsky.social Pre-proof here: www.biologicalpsychiatryjournal.com/article/S000...
#Schizophrenia #Genetics #Psychiatry #PrecisionMedicine #MetaAnalysis

Clinical Genetic Testing in Schizophrenia: A Systematic Review and Meta-Analysis

Genetic testing may provide important diagnostic information for individuals with schizophrenia, but the frequency with which clinically significant variants are identified across different testing ap...

www.biologicalpsychiatryjournal.com

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Aaron Besterman @abesterman.bsky.social · 5d

10/ For clinicians: consider genetics as part of a precision psychiatry approach—useful for prognosis, medical surveillance, reproductive counseling, and occasionally treatment considerations tied to specific variants (see our table of variants with clinical implications).

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Aaron Besterman @abesterman.bsky.social · 5d

9/ What could improve yield over time: comprehensive reporting of both CNVs and SNVs, consistent ACMG/AMP interpretation, and attention to variant classes best captured by GS. As databases mature, VUS reclassification may further increase actionable returns.

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Aaron Besterman @abesterman.bsky.social · 5d

8/ Clinical take-home: These data do not constitute a practice guideline, but they can inform diagnostic workups—especially for schizophrenia with NDD features or early onset—and motivate services to build genetics pathways and counseling capacity.

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Aaron Besterman @abesterman.bsky.social · 5d

7/ Important caveats: substantial heterogeneity (I²≈96%), inconsistent CNV/SNV reporting across studies, and limited geographic representation (notably few data from Latin America, South Asia, Africa). The field needs better standardization and broader sampling.

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Aaron Besterman @abesterman.bsky.social · 5d

6/ Context: The Royal College of Psychiatrists has recommended considering CMA in schizophrenia. Our pooled estimate (~6%) is higher than earlier CNV-only figures, reinforcing that genetic testing can be clinically relevant—but standards and reporting practices matter.

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Aaron Besterman @abesterman.bsky.social · 5d

5/ Who benefits most (signal from meta-regression): higher yields in schizophrenia with co-occurring NDD features—especially intellectual disability—and earlier age of onset. These groups could be prioritized when considering clinical genetic testing.

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Aaron Besterman @abesterman.bsky.social · 5d

4/ Key result: ~6% pooled diagnostic yield (95% CI 4–7%).
By platform: CMA ~6%, ES ~5%, GS ~7%. (Note: confidence intervals overlap; study methods & reporting varied.) This suggests ~1 in 17 patients may receive clinically informative findings.

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Aaron Besterman @abesterman.bsky.social · 5d

3/ What we did: Systematic review & random-effects meta-analysis across MEDLINE, EMBASE, and PsycINFO (2007–2023). We pooled platform-specific yields for chromosomal microarray (CMA), exome (ES), and genome sequencing (GS), and ran meta-regressions to probe heterogeneity.

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Aaron Besterman @abesterman.bsky.social · 5d

2/ Why this matters: genetic testing is now routine in many neurodevelopmental disorders (ID, ASD, epilepsy), yet adoption in schizophrenia has lagged—due to uncertainty about yield, variable reporting, and limited genetics training in psychiatry. We tackle that evidence gap.

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Aaron Besterman @abesterman.bsky.social · 5d

1/ 🚀 New paper out in @BiologicalPsyc1

“Clinical Genetic Testing in Schizophrenia: A Systematic Review and Meta-Analysis.”
We synthesize 31 studies to estimate how often clinical genetic testing returns positive results in schizophrenia.

www.biologicalpsychiatryjournal.com/article/S000...

Clinical Genetic Testing in Schizophrenia: A Systematic Review and Meta-Analysis

Genetic testing may provide important diagnostic information for individuals with schizophrenia, but the frequency with which clinically significant variants are identified across different testing ap...

www.biologicalpsychiatryjournal.com

1

Reposted by Aaron Besterman

Emil Uffelmann @euffelmann.bsky.social · 11d

Our new paper is out, in which we developed an approach to transform Polygenic Scores (PGSs) into disorder probabilities (i.e., the absolute lifetime disorder risk).

Below a thread 👇

open access link: rdcu.be/eIjvC

Estimating disorder probability based on polygenic prediction using the BPC approach

Nature Communications - Here the authors present a method to transform polygenic scores into disorder probabilities using only GWAS summary statistics, genotype data and a prior - no tuning sample...

rdcu.be

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Aaron Besterman @abesterman.bsky.social · Aug 28

12/ SKS & PHTS families who participated

Dr. Julian Martinez-Agosto (UCLA)

@rarediseasectn.bsky.social @rarediseasesint.bsky.social
@autismspeaks.org
@simonsfoundation.org

Home | Developmental Synaptopathies Consortium

Developmental Synaptopathies Consortium works to improve the lives of patients and families affected by developmental synaptopathies.

dsc.rarediseasesnetwork.org

Aaron Besterman @abesterman.bsky.social · Aug 28

11/🏁 Takeaway:
Sensory profiles may provide a window into genetic pathogenicity across OGIDs, but variant scores alone aren’t robust prognostic tools.
Individualized neurobehavioral assessment remains essential for diagnosis, prognosis, and intervention planning.

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Aaron Besterman @abesterman.bsky.social · Aug 28

10/🧩 Clinical classification:
Decision tree using behavioral + medical features (e.g., neonatal teeth for PHTS) performed above chance (CV relative error ≈0.67).
Behavioral-only tree also above chance, showing the strength of detailed phenotyping.

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Aaron Besterman @abesterman.bsky.social · Aug 28

9/Combined OGIDs (SKS + PTEN + PI3K–AKT–MTOR SFARI genes):
• CADD ↗ SSP Low Energy & SSP Total
• CADD ↘ SRS-2 Total T
These were the most consistently stable correlations after 1,000 bootstrap resamples.

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Aaron Besterman @abesterman.bsky.social · Aug 28

8/ PTEN-specific:
• CADD ↗ SSP Low Energy (r=0.72)
• CADD ↘ SRS-2 Total T (r=−0.64)
(both bootstrap-stable; p<0.05 uncorrected)

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Aaron Besterman @abesterman.bsky.social · Aug 28

7/SKS-specific (missense only):
• REVEL ↗ SSP Auditory Filtering (r=0.77)
• AlphaMissense ↗ SSP Visual/Auditory Sensitivity (r=0.74)
• REVEL ↘ DCDQ Control During Movement (r=−0.80)
(all bootstrap-supported; p<0.05 uncorrected)

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Aaron Besterman @abesterman.bsky.social · Aug 28

6/🧬 Pathogenicity scores overall:
Cross-cohort correlations were limited/inconsistent.
CADD showed the most stable associations—especially with sensory processing—supporting the need for deep phenotyping beyond variant scores alone.

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Aaron Besterman @abesterman.bsky.social · Aug 28

5/🔬 Protein-domain findings:
PTEN phosphatase-domain variants → more severe social & executive deficits vs C2-domain variants.
MTOR domain differences (FAT vs PI3K) not significant (sample-size limited in SKS).

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Aaron Besterman @abesterman.bsky.social · Aug 28

4/Cohorts: SKS (MTOR) n=17, PHTS (PTEN) n=74, Macrocephaly-Autism n=33, Controls n=32.
We profiled motor, adaptive, social, executive, sensory domains, ran domain-by-protein analyses, pathogenicity–phenotype correlations, and built diagnostic decision trees.

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Aaron Besterman @abesterman.bsky.social · Aug 28

3/Our central question: How much clinical and genotype–phenotype overlap exists across disorders in the same pathway? Given their rarity, can analyzing them together reveal new insights to improve diagnosis & care?

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Aaron Besterman @abesterman.bsky.social · Aug 28

2/Smith-Kingsmore Syndrome (SKS) is caused by MTOR variants; PTEN Hamartoma Tumor Syndrome (PHTS) by PTEN variants.
Both are overgrowth–intellectual disability syndromes (OGIDs) in the PI3K–AKT–MTOR pathway.

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