Publications by authors named "Elizabeth J Bhoj"

42 Publications

De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.

Mol Autism 2021 Oct 26;12(1):69. Epub 2021 Oct 26.

Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.

Background: De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias.

Methods: Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database.

Results: We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator.

Limitations: The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time.

Conclusions: Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.
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http://dx.doi.org/10.1186/s13229-021-00473-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547031PMC
October 2021

Cleft palate morphology, genetic etiology, and risk of mortality in infants with Robin sequence.

Am J Med Genet A 2021 12 22;185(12):3694-3700. Epub 2021 Jul 22.

Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, WA, USA.

Robin sequence (RS) has many genetic and nongenetic causes, including isolated Robin sequence (iRS), Stickler syndrome (SS), and other syndromes (SyndRS). The purpose of this study was to determine if the presence and type of cleft palate varies between etiologic groups. A secondary endpoint was to determine the relationship of etiologic group, cleft type, and mortality. Retrospective chart review of patients with RS at two high-volume craniofacial centers. 295 patients with RS identified. CP was identified in 97% with iRS, 95% with SS, and 70% of those with SyndRS (p < .0001). U-shaped CP was seen in 86% of iRS, 82% with SS, but only 27% with SyndRS (p < .0001). At one institution, 12 children (6%) with RS died, all from the SyndRS group (p < .0001). All died due to medical comorbidities related to their syndrome. Only 25% of children who died had a U-shaped CP. The most common palatal morphology among those who died was an intact palate. U-shaped CP was most strongly associated with iRS and SS, and with a lower risk of mortality. RS with submucous CP, cleft lip and palate or intact palate was strongly suggestive of an underlying genetic syndrome and higher risk of mortality.
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http://dx.doi.org/10.1002/ajmg.a.62430DOI Listing
December 2021

Pathogenic variants in , a chromatin remodeler, cause a range of syndromic neurodevelopmental features.

Sci Adv 2021 May 12;7(20). Epub 2021 May 12.

Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, USA.

Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in , encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 ortholog led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.
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http://dx.doi.org/10.1126/sciadv.abf2066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115915PMC
May 2021

Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome.

Hum Genet 2021 Jul 3;140(7):1061-1076. Epub 2021 Apr 3.

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.
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http://dx.doi.org/10.1007/s00439-021-02274-3DOI Listing
July 2021

ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes.

J Inherit Metab Dis 2021 07 26;44(4):1001-1012. Epub 2021 Mar 26.

Department of Biochemistry, St. George's University School of Medicine, St. George's, Grenada.

Pathogenic variants in ALG13 (ALG13 UDP-N-acetylglucosaminyltransferase subunit) cause an X-linked congenital disorder of glycosylation (ALG13-CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi-quantitative flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry (ESI-QTOF/MS) N-glycan assay, we report subtle abnormalities in N-glycans that normally account for <0.3% of the total plasma glycans that may increase up to 0.5% in females with the p.(Asn107Ser) variant. Among our 11 unrelated ALG13-CDG individuals, one male had abnormal serum transferrin glycosylation. We describe seven previously unreported subjects including three novel variants in ALG13 and report a milder neurodevelopmental course. We also summarize the molecular, biochemical, and clinical data for the 53 previously reported ALG13-CDG individuals. We provide evidence that ALG13 pathogenic variants may mildly alter N-linked protein glycosylation in both female and male subjects, but the underlying mechanism remains unclear.
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http://dx.doi.org/10.1002/jimd.12378DOI Listing
July 2021

Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies.

Am J Med Genet A 2021 05 8;185(5):1486-1493. Epub 2021 Mar 8.

Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

The RASopathies are a group of similar genetic syndromes with cardiovascular abnormalities, characteristic facial features, short stature, abnormalities of the skin and musculoskeletal system, and variable neurodevelopmental challenges. The most common cardiovascular abnormalities include pulmonary valvular stenosis and hypertrophic cardiomyopathy. Congenital polyvalvular disease (CPVD) refers to congenital dysplasia of two or more cardiac valves. We diagnosed a RASopathy in two individuals with CPVD and noted that CPVD in RASopathies has rarely been reported in the literature. Thus, we performed a retrospective chart review and literature review to investigate the association and characterize the phenotype of CPVD in the RASopathies. CPVD was present in 2.5% (n = 6/243) of individuals in our RASopathy cohort. Involvement of two cardiac valves, commonly the aortic and pulmonic valves, was seen in the majority of individuals (6/8; 75%) in our cohort, but only 27% (3/11) of reported CPVD and RASopathy cases in the literature. CPVD should be considered an associated cardiovascular phenotype of the RASopathies, which has implications for diagnosis and management.
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http://dx.doi.org/10.1002/ajmg.a.62146DOI Listing
May 2021

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community.

Am J Med Genet C Semin Med Genet 2020 12 4;184(4):1030-1041. Epub 2020 Dec 4.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource-limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2-3 clinics per year on various islands in the Caribbean. We also organized a week-long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow-up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.
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http://dx.doi.org/10.1002/ajmg.c.31871DOI Listing
December 2020

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Clinical variability of TUBB-associated disorders: Diagnosis through reanalysis.

Am J Med Genet A 2020 12 5;182(12):3035-3039. Epub 2020 Oct 5.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

A range of clinical findings have been associated with heterozygous mutations in the Beta Tubulin (TUBB) gene, including microcephaly, structural brain abnormalities, intellectual disability, and skin creases. We report a 5-year-old male who presented for evaluation of cleft palate, cardiac defects, growth retardation, hemivertebrae causing scoliosis, and preauricular skin tags. Previous clinical exome sequencing of this patient was nondiagnostic, but reanalysis in the research setting identified a de novo missense c. 925C>G p.(Arg309Gly) mutation in TUBB. This mutation was not found in population allele frequency databases, and was classified to be likely pathogenic. This patient shares some phenotypic characteristics with previous reported patients of TUBB mutations of the two TUBB-related phenotypes: "Cortical dysplasia, complex, with other brain malformations 6" [MIM 615771] and "Circumferential Skin Creases Kunze type (CSC-KT)" [MIM 156610], but has no excess skin creases or structural brain anomalies. We also report previously undescribed features, including transposition of the great arteries and vertebral fusion, thus representing phenotype expansion of TUBB-associated disorders.
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http://dx.doi.org/10.1002/ajmg.a.61897DOI Listing
December 2020

Congenital diaphragmatic hernia as a prominent feature of a SPECC1L-related syndrome.

Am J Med Genet A 2020 12 21;182(12):2919-2925. Epub 2020 Sep 21.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Congenital diaphragmatic hernias (CDH) confer substantial morbidity and mortality. Genetic defects, including chromosomal anomalies, copy number variants, and sequence variants are identified in ~30% of patients with CDH. A genetic etiology is not yet found in 70% of patients, however there is a growing number of genetic syndromes and single gene disorders associated with CDH. While there have been two reported individuals with X-linked Opitz G/BBB syndrome with MID1 mutations who have CDH as an associated feature, CDH appears to be a much more prominent feature of a SPECC1L-related autosomal dominant Opitz G/BBB syndrome. Features unique to autosomal dominant Opitz G/BBB syndrome include branchial fistulae, omphalocele, and a bicornuate uterus. Here we present one new individual and five previously reported individuals with CDH found to have SPECC1L mutations. These cases provide strong evidence that SPECC1L is a bona fide CDH gene. We conclude that a SPECC1L-related Opitz G/BBB syndrome should be considered in any patient with CDH who has additional features of hypertelorism, a prominent forehead, a broad nasal bridge, anteverted nares, cleft lip/palate, branchial fistulae, omphalocele, and/or bicornuate uterus.
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http://dx.doi.org/10.1002/ajmg.a.61878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988837PMC
December 2020

A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly.

Am J Med Genet A 2020 08 2;182(8):1877-1880. Epub 2020 Jul 2.

Department of Biochemistry, St. George's University School of Medicine, St. George's, Grenada.

NALCN encodes a sodium ion leak channel expressed in the nervous system that conducts a persistent influx of sodium ions to facilitate action potential formation. Homozygous or compound heterozygous loss of function variants in NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1; OMIM 615419). Through exome and Sanger sequencing, we found two siblings of Afro-Caribbean ancestry who are homozygous for a known NALCN pathogenic variant, p.Arg735Ter, leading to failure to thrive, severe hypotonia, and dolichocephaly. The older sibling died suddenly without a known etiology after evaluation but before molecular diagnosis. An international collaboration originating from a resource limited Caribbean island facilitated molecular diagnosis. Due to its small population, geographical isolation, and low socioeconomic status, the island lacks many specialty medical services, including clinical genetics. Descriptions of genetic disorders affecting individuals of Afro-Caribbean ancestry are rarely reported in the medical literature. Diagnosis of IHPRF1 is important, as individuals with biallelic pathogenic NALCN variants are severely affected and potentially are at risk for cardiorespiratory arrest. Additionally, knowing the pathogenic variants allows the possibility of prenatal or preimplantation genetic diagnosis.
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http://dx.doi.org/10.1002/ajmg.a.61744DOI Listing
August 2020

Application of exome sequencing to diagnose a novel presentation of the Cornelia de Lange syndrome in an Afro-Caribbean family.

Mol Genet Genomic Med 2020 08 8;8(8):e1318. Epub 2020 Jun 8.

Department of Biochemistry, St. George's University School of Medicine, St. George's, Grenada.

Background: Cornelia de Lange syndrome (CdLS) comprises a recognizable pattern of multiple congenital anomalies caused by variants of the DNA cohesion complex. Affected individuals may display a wide range of phenotypic severity, even within the same family.

Methods: Exome sequencing and confirmatory Sanger sequencing showed the same previously described p.Arg629Ter NIPBL variant in two half-brothers affected with CdLS. Clinical evaluations were obtained in a pro bono genetics clinic.

Results: One brother had relatively mild proportionate limb shortening; the other had complete bilateral hypogenesis of the upper arm with absence of lower arm structures, terminal transverse defects, and no digit remnants. His complex lower limb presentation included long bone deficiency and a deviated left foot. The mother had intellectual disability and microcephaly but lacked facial features diagnostic of the CdLS.

Conclusion: We describe a collaboration between a pediatrics team from a resource-limited nation and USA-based medical geneticists. Reports describing individuals of West Indian ancestry are rarely found in the medical literature. Here, we present a family of Afro-Caribbean ancestry with CdLS presenting with phenotypic variability, including unusual lower limb abnormalities. The observation of this novel family adds to our knowledge of the phenotypic and molecular aspects of CdLS.
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http://dx.doi.org/10.1002/mgg3.1318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434751PMC
August 2020

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy.

Am J Med Genet A 2020 07 5;182(7):1576-1591. Epub 2020 Jun 5.

Department of Otolaryngology, Seattle Children's Hospital, Seattle, Washington, USA.

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.
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http://dx.doi.org/10.1002/ajmg.a.61615DOI Listing
July 2020

Mapping RNA splicing variations in clinically accessible and nonaccessible tissues to facilitate Mendelian disease diagnosis using RNA-seq.

Genet Med 2020 07 30;22(7):1181-1190. Epub 2020 Mar 30.

Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: RNA-seq is a promising approach to improve diagnoses by detecting pathogenic aberrations in RNA splicing that are missed by DNA sequencing. RNA-seq is typically performed on clinically accessible tissues (CATs) from blood and skin. RNA tissue specificity makes it difficult to identify aberrations in relevant but nonaccessible tissues (non-CATs). We determined how RNA-seq from CATs represent splicing in and across genes and non-CATs.

Methods: We quantified RNA splicing in 801 RNA-seq samples from 56 different adult and fetal tissues from Genotype-Tissue Expression Project (GTEx) and ArrayExpress. We identified genes and splicing events in each non-CAT and determined when RNA-seq in each CAT would inadequately represent them. We developed an online resource, MAJIQ-CAT, for exploring our analysis for specific genes and tissues.

Results: In non-CATs, 40.2% of genes have splicing that is inadequately represented by at least one CAT; 6.3% of genes have splicing inadequately represented by all CATs. A majority (52.1%) of inadequately represented genes are lowly expressed in CATs (transcripts per million (TPM) < 1), but 5.8% are inadequately represented despite being well expressed (TPM > 10).

Conclusion: Many splicing events in non-CATs are inadequately evaluated using RNA-seq from CATs. MAJIQ-CAT allows users to explore which accessible tissues, if any, best represent splicing in genes and tissues of interest.
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http://dx.doi.org/10.1038/s41436-020-0780-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335339PMC
July 2020

Imprinted genes in clinical exome sequencing: Review of 538 cases and exploration of mouse-human conservation in the identification of novel human disease loci.

Eur J Med Genet 2020 Jun 10;63(6):103903. Epub 2020 Mar 10.

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 4, Boston, MA, 02115, USA. Electronic address:

Human imprinting disorders cause a range of dysmorphic and neurocognitive phenotypes, and they may elude traditional molecular diagnosis such exome sequencing. The discovery of novel disorders related to imprinted genes has lagged behind traditional Mendelian disorders because current diagnostic technology, especially unbiased testing, has limited utility in their discovery. To identify novel imprinting disorders, we reviewed data for every human gene hypothesized to be imprinted, identified each mouse ortholog, determined its imprinting status in the mouse, and analyzed its function in humans and mice. We identified 17 human genes that are imprinted in both humans and mice, and have functional data in mice or humans to suggest that dysregulated expression would lead to an abnormal phenotype in humans. These 17 genes, along with known imprinted genes, were preferentially flagged 538 clinical exome sequencing tests. The identified genes were: DIRAS3 [1p31.3], TP73 [1p36.32], SLC22A3 [6q25.3], GRB10 [7p12.1], DDC [7p12.2], MAGI2 [7q21.11], PEG10 [7q21.3], PPP1R9A [7q21.3], CALCR [7q21.3], DLGAP2 [8p23.3], GLIS3 [9p24.2], INPP5F [10q26.11], ANO1 [11q13.3], SLC38A4 [12q13.11], GATM [15q21.1], PEG3 [19q13.43], and NLRP2 [19q13.42]. In the 538 clinical cases, eight cases (1.7%) reported variants in a causative known imprinted gene. There were 367/758 variants (48.4%) in imprinted genes that were not known to cause disease, but none of those variants met the criteria for clinical reporting. Imprinted disorders play a significant role in human disease, and additional human imprinted disorders remain to be discovered. Therefore, evolutionary conservation is a potential tool to identify novel genes involved in human imprinting disorders and to identify them in clinical testing.
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http://dx.doi.org/10.1016/j.ejmg.2020.103903DOI Listing
June 2020

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.

Genet Med 2020 03 3;22(3):524-537. Epub 2019 Oct 3.

CHU de Rennes, service de génétique clinique, Rennes, France.

Purpose: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.

Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated.

Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.

Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
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http://dx.doi.org/10.1038/s41436-019-0657-0DOI Listing
March 2020

ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor.

Nat Med 2019 07 1;25(7):1116-1122. Epub 2019 Jul 1.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.
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http://dx.doi.org/10.1038/s41591-019-0479-2DOI Listing
July 2019

Muenke syndrome: Medical and surgical comorbidities and long-term management.

Am J Med Genet A 2019 08 20;179(8):1442-1450. Epub 2019 May 20.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children's Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives.
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http://dx.doi.org/10.1002/ajmg.a.61199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959001PMC
August 2019

Automated Clinical Exome Reanalysis Reveals Novel Diagnoses.

J Mol Diagn 2019 01;21(1):38-48

Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Clinical exome sequencing (CES) has a reported diagnostic yield of 20% to 30% for most clinical indications. The ongoing discovery of novel gene-disease and variant-disease associations are expected to increase the diagnostic yield of CES. Performing systematic reanalysis of previously nondiagnostic CES samples represents a significant challenge for clinical laboratories. Here, we present the results of a novel automated reanalysis methodology applied to 300 CES samples initially analyzed between June 2014 and September 2016. Application of our reanalysis methodology reduced reanalysis variant analysis burden by >93% and correctly captured 70 of 70 previously identified diagnostic variants among 60 samples with previously identified diagnoses. Notably, reanalysis of 240 initially nondiagnostic samples using information available on July 1, 2017, revealed 38 novel diagnoses, representing a 15.8% increase in diagnostic yield. Modeling monthly iterative reanalysis of 240 nondiagnostic samples revealed a diagnostic rate of 0.57% of samples per month. Modeling the workload required for monthly iterative reanalysis of nondiagnostic samples revealed a variant analysis burden of approximately 5 variants/month for proband-only and approximately 0.5 variants/month for trio samples. Approximately 45% of samples required evaluation during each monthly interval, and 61.3% of samples were reevaluated across three consecutive reanalyses. In sum, automated reanalysis methods can facilitate efficient reevaluation of nondiagnostic samples using up-to-date literature and can provide significant value to clinical laboratories.
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http://dx.doi.org/10.1016/j.jmoldx.2018.07.008DOI Listing
January 2019

Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes.

Eur J Med Genet 2019 Dec 22;62(12):103588. Epub 2018 Nov 22.

Department of Genetics, APHP-Robert DEBRE University Hospital, Sorbonne Paris-Cité University, and INSERM UMR 1141, Paris, France. Electronic address:

The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome" as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities.
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http://dx.doi.org/10.1016/j.ejmg.2018.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594898PMC
December 2019

Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma.

Am J Med Genet A 2018 12 18;176(12):2710-2719. Epub 2018 Nov 18.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss-of-function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation-positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow-growing hypothalamo-pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.
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http://dx.doi.org/10.1002/ajmg.a.40644DOI Listing
December 2018

An Algorithm for the Assessment of Facial Asymmetry in Children With Focus on Etiology and Treatment.

Cleft Palate Craniofac J 2019 03 11;56(3):419-424. Epub 2018 May 11.

2 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Facial asymmetry is a common referral indication for craniofacial teams but has a wide range of causes. Prompt identification of etiology is critical to treatment, as medical and surgical interventions vary depending on the cause of asymmetry in each patient.

Solution: A standardized diagnostic algorithm.

What We Did That Is New: We developed an algorithm to assist in the diagnostic evaluation of facial asymmetry with a focus on next steps for medically actionable causes.
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http://dx.doi.org/10.1177/1055665618775725DOI Listing
March 2019

De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies.

Am J Med Genet A 2018 04 15;176(4):969-972. Epub 2018 Feb 15.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.
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http://dx.doi.org/10.1002/ajmg.a.38620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867271PMC
April 2018

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Am J Hum Genet 2017 Dec 30;101(6):985-994. Epub 2017 Nov 30.

Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812889PMC
December 2017

Expanding the phenotypic spectrum of TP63-related disorders including the first set of monozygotic twins.

Am J Med Genet A 2018 01 12;176(1):75-81. Epub 2017 Nov 12.

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay-Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T-cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63-related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63-related disorders, as it was reported in one prior individual and two of the individuals in our case series.
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http://dx.doi.org/10.1002/ajmg.a.38516DOI Listing
January 2018

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

Am J Hum Genet 2017 Nov;101(5):768-788

Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham NG5 1PB, UK.

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673671PMC
November 2017

A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.

Sci Rep 2017 06 19;7(1):3847. Epub 2017 Jun 19.

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.
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http://dx.doi.org/10.1038/s41598-017-01674-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476671PMC
June 2017

Phenotypic predictors and final diagnoses in patients referred for RASopathy testing by targeted next-generation sequencing.

Genet Med 2017 06 20;19(6):715-718. Epub 2016 Oct 20.

Division of Genomic Diagnostics and Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Introduction: RASopathies include disorders generally characterized by developmental delay, specific heart defects, short stature, cardiac hypertrophy, and facial dysmorphisms. Next-generation sequencing (NGS)-based panels have widespread acceptance as a diagnostic tool for RASopathies.

Materials And Methods: The first 126 patients evaluated by clinical examination and the NGS RASopathy panel at the Children's Hospital of Philadelphia were enrolled. We calculated diagnosis rate, correlated reported clinical findings with positive or negative test results, and identified final molecular diagnoses in 28/96 patients who tested negative for RASopathies.

Results: Twenty-four patients had pathogenic variants on the RASopathy panel, for a diagnostic yield of 19%. Reported features of pulmonic stenosis and ptosis were significantly correlated with a positive test result; no reported features were significantly correlated with a negative test result. We identified 27 different alternative diagnoses for patients originally suspected of having RASopathies.

Discussion: This study provides information that can assist in guiding differential diagnosis and genetic testing for patients suspected of having a RASopathy disorder.Genet Med advance online publication 20 October 2016.
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http://dx.doi.org/10.1038/gim.2016.169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095193PMC
June 2017
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