Applicability: This guidance applies to all current or potential de novo state member banks and insured depository institutions that are or plan to become member banks of the Federal Reserve System, including those with $10 billion or less in total consolidated assets.
This letter1 provides guidance to Federal Reserve Banks regarding the supervision of de novo state member banks (de novos), and the evaluation of de novo insured depository institutions2 seeking to become state member banks. For purposes of this letter, an insured depository institution is considered to be in the de novo stage until it has been operating for at least three years.3 Further, this letter applies to any commercial bank, thrift, Edge Act corporation, or industrial bank that has been in existence for less than three years and is converting to become a state member bank.
After the initial target examination, the next three examinations of the de novo, either led by the Federal Reserve or conducted jointly with the state banking department, should be full-scope. In addition to the supervisory expectations for a full-scope examination, the Reserve Bank should review the de novo for the following items.
This policy applies to de novos that are subsidiaries of existing bank holding companies. A Reserve Bank may, however, elect to make a risk-based determination that a de novo that is a subsidiary of a bank holding company with consolidated assets of greater than $3 billion should be examined less frequently than otherwise suggested in this guidance if, in the opinion of the Reserve Bank, the parent company and its subsidiary banks are in satisfactory condition and the parent is considered to be a source of strength to its insured depository institution subsidiaries. Such subsidiary de novos would be expected to maintain capital levels in conformance with the de novo policy guideline.
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.
We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.
In this study, we describe the identification of TCF20 pathogenic variations by either clinical exome sequencing (ES) or clinical chromosomal microarray analysis (CMA) from clinically ascertained subjects consisting of cohorts of patients presenting with neurodevelopmental disorders as the major phenotype as well as with various other suspected genetic disorders. We report the clinical and molecular characterization of 28 subjects with TCF20 de novo or inherited pathogenic single nucleotide variants/indels (SNV/indels) and 4 subjects with interstitial deletions involving TCF20. These subjects present with a core phenotype of DD/ID, dysmorphic facial features, congenital hypotonia, and variable neurological disturbances including ataxia, seizures, and movement disorders; some patients presented features including sleep issues resembling those observed in SMS. Additionally, we report the molecular findings of 10 anonymized subjects with pathogenic TCF20 SNVs or deletion/duplication copy-number variants (CNVs). We demonstrate that ascertainment of patients from clinical cohorts driven by molecular diagnostic findings (TCF20 LoF variants) delineates the phenotypic spectrum of a potentially novel syndromic disorder.
Immunophenotypic classification of acute lymphoblastic leukemia (ALL) has well-recognized prognostic implications. The significance of CD20 expression has been evaluated in childhood precursor B-lineage ALL with conflicting results. We retrospectively analyzed the influence of CD20 expression on outcome in 253 adults with de novo precursor B-lineage ALL treated with either conventional (VAD/CVAD) or intensive (hyper-CVAD) frontline chemotherapy regimens in the pre-rituximab era. Overall, CD20 positivity of at least 20% was associated with lower 3-year rates of complete remission duration (CRD; 20% vs 55%, P < .001) and overall survival (OS; 27% vs 40%, p = .03). In the CD20 negative subset, the 3-year rates for CRD (58% vs 42%, p = .04) and OS (60% vs 28%, P < .001) were superior for hyper-CVAD compared with VAD/CVAD; rates were particularly favorable for the CD20 negative younger age group (68% and 85%, respectively). In contrast, 3-year CRD and OS rates were uniformly poor for the CD20-positive group regardless of therapy (27% or less). Multivariate analysis for event-free survival identified older age, leukocyte count higher than 30 x 10(9)/L, presence of Philadelphia chromosome, high systemic risk classification, and CD20 positivity as independent predictors of worse outcome. In conclusion, CD20 expression in de novo adult precursor B-lineage ALL appears to be associated with a poor prognosis. Incorporation of monoclonal antibodies directed against CD20 into frontline chemotherapy regimens warrants investigation.
Here, we report two independent individuals with ID in whom de novo nonsense and frameshift variants of TCF20 were identified by trio whole exome sequencing (WES). We considerably expand the clinical picture of individuals with de novo variants of TCF20, in particular regarding growth anomalies and the incidence of ID.
Bidirectional Sanger sequencing of TCF20 variants was performed using the ABI BigDye Terminator v.3.1 Cycle Sequencing Kit (Life Technologies, Carlsbad, CA, USA) to verify the variants and their de novo status. For individual 1 and his parents, whole blood genomic DNA was analysed, and for individual 2 and his parents, genomic DNA extracted from whole blood, buccal swaps and saliva. Primer sequences are available upon request.
The two individuals with de novo TCF20 variants presented here share a phenotype of mild ID, secondary tall stature, postnatal macrocephaly, obesity and muscular hypotonia. Only one of them has ASD and seizures. Neither organ malformations nor major dysmorphism were present.
The inclusion criterion of the first study reporting TCF20 variants was ASD; therefore, all probands with de novo TCF20 variants in that report had presented with this phenotype.1 The reported variants included a de novo missense and a de novo frameshift variants (Figure 2) as well as two disruptions caused by an inversion breakpoint, which had arisen from parental germline mosaicism. Normal intelligence was reported for the individual with the missense variant while the remaining, more deleterious variants were associated with ID or borderline intellectual functioning. Interestingly, two of the probands had craniosynostosis. No further clinical data were provided.
Our identification of de novo nonsense and frameshift TCF20 variants in two clinically well-characterised individuals considerably expands the known clinical picture. In addition to their mild ID, both individuals shared previously undescribed physical findings such as tall stature, macrocephaly, obesity and muscular hypotonia. In contrast to the first study, only one of the present individuals had ASD. Amongst all known six individuals with de novo TCF20 variants, ID/DD and ASD are equally prevalent (five out of six, respectively). All three frameshift and nonsense variants were associated with ID and only two of them with ASD. Given that in the present sample two deleterious variants were identified in 313 ID patients compared with one missense variant in the 342 ASD probands reported previously,1 de novo truncating TCF20 variants may be more frequent in ID/DD than in ASD.
A de novo origin of the two TCF20 loss-of-function variants is highly probable because no evidence for parental mosaicism was found in high-coverage WES data or by sequencing saliva and buccal mucosa DNA. The sequencing results of buccal mucosa and saliva DNA of individual 2 were identical to the results of the peripheral blood DNA sequencing, pointing to a germline or early postzygotic origin. Comprehensive chromosomal microarray analyses and WES analyses of the two individuals gave no evidence that other genetic factors noticeably contribute to the phenotype. The broad phenotypic overlap of the two individuals may also be regarded as an argument for a monocausal aetiology. However, a modification of the phenotype or minor contribution of other exogenous or genetic factors such as the compound heterozygous or hemizygous X-linked variants discovered by WES cannot be excluded entirely. Other than the TCF20 loss-of-function mutations, no common potential aetiological factors were identified except for compound heterozygous variants in CMYA5 (cardiomyopathy associated 5), a gene without known associations with ID/DD and many compound heterozygous variants amongst in-house controls. Taken together, no convincing evidence for digenic, oligogenic or multifactorial models of inheritance was found and an autosomal dominant mode of inheritance with high penetrance seems highly probable. 781b155fdc