Suha Bachir

All Publications

• Psychotic Features in Myhre Syndrome: Evidence for Broader Neuropsychiatric Surveillance. American journal of medical genetics. Part C, Seminars in medical genetics Ebuen, M., Krishnan, V., Irby, K., Monsberger, R., Hopkin, R. J., Brand, M. R., Friedman, N., Thom, R. P., Reiss, A. L., Algaze, C., Bernstein, J. A., Alexander, S., Cormier-Daire, V., Lin, A. E., Bachir, S. 2026

  Abstract

  Myhre syndrome is a rare genetic disorder caused by pathogenic variants in SMAD4. The neurocognitive profile may include intellectual disability and developmental delay across a wide spectrum of domains. Four individuals with Myhre syndrome and psychosis and/or schizophrenia have been reported. We discuss three additional individuals (one briefly mentioned in a review of patients with Myhre syndrome) with SMAD4 pathogenic variants at codon Arg496Cys (two cases) and codon Ile500Val (one case). All had social challenges and variable developmental delays. They presented with acute-onset psychosis and were diagnosed with either psychosis, not otherwise specified, or psychosis associated with bipolar disorder. The seven individuals (5 female, 2 male) ranged in age from 13 to 24 years (mean 18.7 years) and had variable responses to pharmacologic and behavioral interventions. The underlying mechanism of psychosis in Myhre syndrome may be due to disruptions in the TGF-β signaling pathway, which involves the interactions of TGF-β family members and SMAD proteins, including SMAD4. Although additional cases are needed to verify our observations, psychosis may be a component of the neurodevelopmental phenotype of Myhre syndrome, highlighting the importance of rapid psychiatric evaluation and intervention.

  View details for DOI 10.1002/ajmg.c.70011

  View details for PubMedID 42267964

• Biallelic LAMP3 Variants in Five Families with Interstitial Lung Disease: Evidence of a Disease-Gene Association. Genetics in medicine : official journal of the American College of Medical Genetics Keehan, L. A., Ono-Minagi, H., Hadhud, M., Rips, J., Hinds, D. M., Fischer, A. J., Bartlett, J. A., McCray, P. B., Qawasmi, N., Nathan, N., Louvrier, C., Desroziers, T., Damme, M., Griese, M., Wegner, D. J., Cole, F. S., Wambach, J. A., Wheeler, M. T., Burbelo, P. D., Bonner, D. E., Bernstein, J. A., Chiorini, J. A., Breuer, O., Milla, C. 2026: 102531

  Abstract

  Genetic causes of surfactant dysfunction are associated with childhood interstitial lung disease (chILD). Lysosome-associated membrane glycoprotein 3 (LAMP3) is highly expressed within lamellar bodies of alveolar epithelial type II cells, and variants in LAMP3 have recently been suggested as a novel cause of chILD. This study describes the phenotypes of participants with biallelic variants in LAMP3 and presents functional studies evaluating the role of specific LAMP3 variants.Phenotypic data was collected through chart review and clinical evaluation. In vitro effects of LAMP3 variants were evaluated through immunohistochemistry, WB, and flow cytometry.Thirteen participants were identified with biallelic variants in LAMP3. They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. All symptomatic participants demonstrated ground glass opacities early in life and lung fibrosis later in life. For one participant, BAL analysis showed abnormal surfactant protein composition and lung biopsy revealed irregular LB. In vitro studies in lung epithelial cells with induced expression of specific LAMP3 variants demonstrated reduced protein expression and abnormal glycosylation.Biallelic LAMP3 variants are associated with an interstitial lung disease phenotype with variable expressivity. Evaluation for LAMP3 variants should be considered in individuals with unexplained interstitial lung disease.

  View details for DOI 10.1016/j.gim.2026.102531

  View details for PubMedID 41653023

• An optimized variant prioritization process for rare disease diagnostics: recommendations for Exomiser and Genomiser. Genome medicine Cooperstein, I. B., Marwaha, S., Ward, A., Kobren, S. N., Carter, J. N., Wheeler, M. T., Marth, G. T. 2025; 17 (1): 127

  Abstract

  Exome sequencing (ES) and genome sequencing (GS) are increasingly used as standard genetic tests to identify diagnostic variants in rare disease cases. However, prioritizing these variants to reduce the time and burden of manual interpretation by clinical teams remains a significant challenge. The Exomiser/Genomiser software suite is the most widely adopted open-source software for prioritizing coding and noncoding variants. Despite its ubiquitous use, limited data-driven guidelines currently exist to optimize its performance for diagnostic variant prioritization. Based on detailed analyses of Undiagnosed Diseases Network (UDN) probands, this study presents optimized parameters and practical recommendations for deploying the Exomiser and Genomiser tools. We also highlight scenarios where diagnostic variants may be missed and propose alternative workflows to improve diagnostic success in such complex cases.We analyzed 386 diagnosed probands from the UDN, including cases with coding and noncoding diagnostic variants. We systematically evaluated how tool performance was affected by key parameters, including gene:phenotype association data, variant pathogenicity predictors, phenotype term quality and quantity, and the inclusion and accuracy of family variant data.Parameter optimization significantly improved Exomiser's performance over default parameters. For GS data, the percentage of coding diagnostic variants ranked within the top 10 candidates increased from 49.7% to 85.5%, and for ES, from 67.3% to 88.2%. For noncoding variants prioritized with Genomiser, the top 10 rankings improved from 15.0% to 40.0%. We also explored refinement strategies for Exomiser outputs, including using p-value thresholds and flagging genes that are frequently ranked in the top 30 candidates but rarely associated with diagnoses.This study provides an evidence-based framework for variant prioritization in ES and GS data using Exomiser and Genomiser. These recommendations have been implemented in the Mosaic platform to support the ongoing analysis of undiagnosed UDN participants and provide efficient, scalable reanalysis to improve diagnostic yield. Our work also highlights the importance of tracking solved cases and diagnostic variants that can be used to benchmark bioinformatics tools. Exomiser and Genomiser are available at https://github.com/exomiser/Exomiser/ .

  View details for DOI 10.1186/s13073-025-01546-1

  View details for PubMedID 41121346

  View details for PubMedCentralID PMC12539062

• RAPSN-Associated Congenital Myasthenic Syndrome due to Biallelic Single Nucleotide Variants at the Same Position. Case reports in genetics Keehan, L., Carter, J. N., Kravets, E., Wheeler, M. T., Bernstein, J. A., Maselli, R. A., Sampson, J. B., Bachir, S. 2025; 2025: 1882021

  Abstract

  Biallelic pathogenic variants in RAPSN cause a form of congenital myasthenic syndrome (CMS), which is typically characterized by fatiguable muscle weakness, hypotonia, and feeding difficulties that present in the neonatal period or early childhood. RAPSN-associated CMS can be treated with acetylcholinesterase inhibitors. Here, we present a 4-year-old male with a history of neonatal respiratory distress, hypotonia, and muscle weakness exacerbated by illness who underwent trio genome sequencing and was found to have biallelic single nucleotide variants at the same position in RAPSN, encoding NM_005055.5:c.264C > A p.(N88K) and NM_005055.5:c.264C > G p.(N88K). The paternally inherited c.264C > G variant has not been previously reported. Interestingly, only the maternally inherited c.264C > A variant was reported on the patient's prior clinical exome sequencing, which delayed diagnosis and initiation of treatment for this patient. This case highlights the complexity of identifying multiallelic variants during exome and genome sequencing analysis. Additionally, this case is the first report of facial malformations in a patient with RAPSN-associated CMS due to variants outside of the promoter region. Trial Registration: ClinicalTrials.gov identifier: NCT02450851.

  View details for DOI 10.1155/crig/1882021

  View details for PubMedID 41158980

  View details for PubMedCentralID PMC12558694

• Fetal phenotype and diagnosis of autosomal dominant Robinow syndrome due to novel DVL1 variant. Prenatal diagnosis Smith, C. M., Guinon, K., Bachir, S., Tise, C. G. 2024

  Abstract

  Due to abnormal prenatal ultrasound findings of femoral shortening and flattened facial profile, a G2P0 pregnant patient underwent an amniocentesis at 15 weeks of gestation for proband-only exome sequencing. Bioinformatic filtering for genes included on the laboratory's extended skeletal dysplasia panel identified a heterozygous, likely pathogenic, frameshift variant in DVL1 NM_001330311.2:c.1575_1582dup; (p.Pro528ArgfsTer149). Pathogenic variants in DVL1 are associated with autosomal dominant Robinow syndrome (ADRS), a genetic disorder characterized by skeletal dysplasia with genital and craniofacial abnormalities. Prenatal ultrasound in the third trimester noted shortened long bones (first percentile for gestational age), macrocephaly with frontal bossing, short and upturned nose with a wide nasal root, triangular mouth, low pedal arches concerning for rocker-bottom feet, and ambiguous genitalia. A postnatal exam by Medical Genetics confirmed the prenatal findings in addition to hypertelorism, brachydactyly with broad thumbs and halluces, clinodactyly of second fingers, rigid gums with a frontal frenulum, and a sacral dimple. This case describes a novel variant in DVL1 identified in a fetus with prenatal and postnatal phenotypic features consistent with ADRS. To our knowledge, this is the first reported case of a prenatal molecular diagnosis of the dominant form of Robinow syndrome and the third case to describe prenatal ultrasound findings associated with this diagnosis.

  View details for DOI 10.1002/pd.6632

  View details for PubMedID 38982229