- Clinical Molecular Genetics
- Clinical Cytogenetics
- Clinical Pathology
Clinical Associate Professor, Pathology
Fellowship: UCLA David Geffen School Of Medicine Registrar (2006) CA
Fellowship: UCLA David Geffen School Of Medicine Registrar (2005) CA
PhD Training: Albert Einstein College of Medicine (2002) NY
Board Certification, Clinical Molecular Genetics, American Board of Medical Genetics and Genomics (2007)
Board Certification: American Board of Medical Genetics and Genomics, Clinical Cytogenetics (2005)
Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder.
Genetics in medicine : official journal of the American College of Medical Genetics
SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease.Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher.Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present.We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.
View details for DOI 10.1016/j.gim.2022.04.011
View details for PubMedID 35567594
Best practices for the interpretation and reporting of clinical whole genome sequencing.
NPJ genomic medicine
2022; 7 (1): 27
Whole genome sequencing (WGS) shows promise as a first-tier diagnostic test for patients with rare genetic disorders. However, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading health care and research organizations in the US and Canada, was formed to expand access to high quality clinical WGS by convening experts and publishing best practices. Here, we present best practice recommendations for the interpretation and reporting of clinical diagnostic WGS, including discussion of challenges and emerging approaches that will be critical to harness the full potential of this comprehensive test.
View details for DOI 10.1038/s41525-022-00295-z
View details for PubMedID 35395838
Accelerated identification of disease-causing variants with ultra-rapid nanopore genome sequencing.
Whole-genome sequencing (WGS) can identify variants that cause genetic disease, but the time required for sequencing and analysis has been a barrier to its use in acutely ill patients. In the present study, we develop an approach for ultra-rapid nanopore WGS that combines an optimized sample preparation protocol, distributing sequencing over 48 flow cells, near real-time base calling and alignment, accelerated variant calling and fast variant filtration for efficient manual review. Application to two example clinical cases identified a candidate variant in <8 h from sample preparation to variant identification. We show that this framework provides accurate variant calls and efficient prioritization, and accelerates diagnostic clinical genome sequencing twofold compared with previous approaches.
View details for DOI 10.1038/s41587-022-01221-5
View details for PubMedID 35347328
- Ultra-Rapid Nanopore Whole Genome Genetic Diagnosis of Dilated Cardiomyopathy in an Adolescent With Cardiogenic Shock. Circulation. Genomic and precision medicine 2022: CIRCGEN121003591
- Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting. The New England journal of medicine 2022
Comparison of the Transcriptomic Signatures in Pediatric and Adult CML.
1800; 13 (24)
Children with chronic myeloid leukemia (CML) tend to present with higher white blood counts and larger spleens than adults with CML, suggesting that the biology of pediatric and adult CML may differ. To investigate whether pediatric and adult CML have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML CD34+ cells and healthy pediatric and adult CD34+ control cells. Using high-throughput RNA sequencing, we found 567 genes (207 up- and 360 downregulated) differentially expressed in pediatric CML CD34+ cells compared to pediatric healthy CD34+ cells. Directly comparing pediatric and adult CML CD34+ cells, 398 genes (258 up- and 140 downregulated), including many in the Rho pathway, were differentially expressed in pediatric CML CD34+ cells. Using RT-qPCR to verify differentially expressed genes, VAV2 and ARHGAP27 were significantly upregulated in adult CML CD34+ cells compared to pediatric CML CD34+ cells. NCF1, CYBB, and S100A8 were upregulated in adult CML CD34+ cells but not in pediatric CML CD34+ cells, compared to healthy controls. In contrast, DLC1 was significantly upregulated in pediatric CML CD34+ cells but not in adult CML CD34+ cells, compared to healthy controls. These results demonstrate unique molecular characteristics of pediatric CML, such as dysregulation of the Rho pathway, which may contribute to clinical differences between pediatric and adult patients.
View details for DOI 10.3390/cancers13246263
View details for PubMedID 34944883
Identification of a pathogenic TUBB1 variant in a Chinese family with congenital macrothrombocytopenia through whole genome sequencing.
Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. We herein report a large Chinese family presented with phenotypic variability involving thrombocytopenia and/or giant platelets. Whole genome sequencing (WGS) of the proband and one of his affected brothers identified a potentially pathogenic c.952 C > T heterozygous variant in the TUBB1 gene. This p.R318W β1-tubulin variant was also identified in three additional siblings and five members of the next generation. These findings were consistent with an autosomal dominant inheritance with incomplete penetrance. Moreover, impaired platelet agglutination in response to ristocetin was detected in the patient's brother. Half of the family members harboring the p.R318W mutation displayed significantly decreased external release of p-selectin by stimulated platelets. The p.R318W β1-tubulin mutation was identified for the first time in a Chinese family with congenital macrothrombocytopenia using WGS as an unbiased sequencing approach. Affected individuals within the family demonstrated impaired platelet aggregation and/or release functions.
View details for DOI 10.1080/09537104.2020.1869714
View details for PubMedID 33400601
Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay.
Genetics in medicine : official journal of the American College of Medical Genetics
To identify novel genes associated with intellectual disability (ID) in four unrelated families.Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A.Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay. Other clinical features included hypotonia, short stature, seizures, and behavior disorder. Characteristic features were appreciated in some individuals but not all; in some cases, features became more apparent with age. We demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioral abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.These data indicate that biallelic loss-of-function variants in UBE4A cause a novel intellectual disability syndrome, suggesting that UBE4A enzyme activity is required for normal development and neurological function.
View details for DOI 10.1038/s41436-020-01047-z
View details for PubMedID 33420346