Aaron Besterman

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.

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...

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

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...

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

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).

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.

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.

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.

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.

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.

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.

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.

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.

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...

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...

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

12/ SKS & PHTS families who participated

Dr. Julian Martinez-Agosto (UCLA)

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

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.

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.

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.

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)

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)

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.

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).

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.

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?

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.

Neurobehavioral Signatures in Overgrowth Intellectual Disability Syndromes: Dissecting Genotype-Phenotype Relationships in the PI3K-AKT-MTOR Pathway Overgrowth intellectual disability syndromes (OGIDs) caused by mutations in the PI3K-AKT-MTOR pathway present significant neurobehavioral challenges. While PTEN Hamartoma Tumor Syndrome (PHTS) has bee...

1/
Thrilled to share our preprint:
“Neurobehavioral Signatures in Overgrowth Intellectual Disability Syndromes: Dissecting Genotype–Phenotype Relationships in the PI3K–AKT–MTOR Pathway.”
🔗

www.medrxiv.org/content/10.1...

Long-Read Genome Sequencing in Clinical Psychiatry: RFX3 Haploinsufficiency in a Hospitalized Adolescent With Autism, Intellectual Disability, and Behavioral Decompensation - PubMed Long-Read Genome Sequencing in Clinical Psychiatry: RFX3 Haploinsufficiency in a Hospitalized Adolescent With Autism, Intellectual Disability, and Behavioral Decompensation

We and @abesterman.bsky.social detected a TAN-DUP-DEL in a clinical case. Assembly of the complex SV was essential for determining the genetic diagnosis of RFX3 haploinsufficiency. It showed that the DEL occured within the FUNCTIONAL copy of the gene pubmed.ncbi.nlm.nih.gov/40200712/

Structural variants are significant contributor to autism. But many SVs & TRs are hard to detect with short reads. Long read sequencing with @pacbio.bsky.social and @nanoporetech.com captures and maps out alot of what short reads miss. So what can LR-WGS tell us about autism? 🧵

Excited about our new preprint: 1st successful genome-wide study of >61,000 panic attack and 29,000 panic disorder cases. www.medrxiv.org/content/10.1... We find 17 associations & evidence that peripheral neurons in eye, lungs and heart are involved in panic & other psychiatric disorders 1/n

Saturation genome editing of RNU4-2 reveals distinct dominant and recessive neurodevelopmental disorders Recently, de novo variants in an 18 nucleotide region in the centre of RNU4-2 were shown to cause ReNU syndrome, a syndromic neurodevelopmental disorder (NDD) that is predicted to affect tens of thous...

🚨I could not be more excited to share our new preprint on saturation genome editing of the small nuclear RNA (snRNA) RNU4-2:
www.medrxiv.org/content/10.1...

A super fun collaboration with incredible duo @gregfindlay.bsky.social @joachimdejonghe.bsky.social from @crick.ac.uk
🧬🖥️🩺

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