Exome sequencing of a single individual for a clinical indication may result in the identification of incidental deleterious variants unrelated to the indication for testing (secondary findings). ...Given the recent availability of clinical exome testing, there is a limited knowledge regarding the disclosure preferences and impact of secondary findings in a clinical diagnostic setting. In this article, we provide preliminary data regarding the preferences for secondary findings results disclosure based on the first 200 families referred to Ambry Genetics for diagnostic exome sequencing.
Secondary findings were categorized into four groups in the diagnostic exome sequencing consent: carrier status of recessive disorders, predisposition to later-onset disease, predisposition to increased cancer risk, and early-onset disease. In this study, we performed a retrospective analysis of patient responses regarding the preferences for secondary findings disclosure.
The majority of patients (187/200; 93.5%) chose to receive secondary results for one or more available categories. Adult probands were more likely than children to opt for blinding of secondary data (16 vs. 4%, respectively). Among responses for blinding, preferences were evenly scattered among categories.
These data represent the unprecedented results of a large reference laboratory providing clinical exome sequencing. We report, for the first time, the preferences of patients and families for the receipt of secondary findings based on clinical genome sequencing. Overwhelmingly, families undergoing exome sequencing opt for the disclosure of secondary findings. The data may have implications regarding the development of guidelines for secondary findings reporting among patients with severe and/or life-threatening disease undergoing clinical genomic sequencing.
We describe a novel congenital motor neuron disease with early demise due to respiratory insufficiency with clinical overlap with spinal muscular atrophy with respiratory distress (SMARD) type 1 but ...lacking a mutation in the IGHMBP2 gene.
Exome sequencing was used to identify a de novo mutation in the LAS1L gene in the proband. Pathogenicity of the mutation was validated using a zebrafish model by morpholino-mediated knockdown of las1l.
We identified a de novo mutation in the X-linked LAS1L gene in the proband (p.S477N). The mutation is in a highly conserved region of the LAS1L gene predicted to be deleterious by bioinformatic analysis. Morpholino-based knockdown of las1l, the orthologous gene in zebrafish, results in early lethality and disruption of muscle and peripheral nerve architecture. Coinjection of wild-type but not mutant human RNA results in partial rescue of the phenotype.
We report a patient with a SMARD phenotype due to a mutation in LAS1L, a gene important in coordinating processing of the 45S pre-rRNA and maturation of the large 60S ribosomal subunit. Similarly, the IGHMB2 gene associated with SMARD type 1 has been suggested to have an important role in ribosomal biogenesis from its role in processing the 45S pre-rRNA. We propose that disruption of ribosomal maturation may be a common pathogenic mechanism linking SMARD phenotypes caused by both IGHMBP2 and LAS1L.
Neonatal patients are particularly appropriate for utilization of diagnostic exome sequencing (DES), as many Mendelian diseases are known to present in this period of life but often with complex, ...heterogeneous features. We attempted to determine the diagnostic rates and features of neonatal patients undergoing DES.
The clinical histories and results of 66 neonatal patients undergoing DES were retrospectively reviewed.
Clinical DES identified potentially relevant findings in 25 patients (37.9%). The majority of patients had structural anomalies such as birth defects, dysmorphic features, cardiac, craniofacial, and skeletal defects. The average time for clinical rapid testing was 8 days.
Our observations demonstrate the utility of family-based exome sequencing in neonatal patients, including familial cosegregation analysis and comprehensive medical review.
Biallelic mutations of
UBE3B
have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis–ptosis–intellectual disability syndrome), an autosomal recessive ...condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous
UBE3B
mutations in six additional patients from five unrelated families using either targeted
UBE3B
sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the
UBE3B
-related disorder in several ways. First, we have identified
UBE3B
mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello–Carey syndrome as well as the patient reported to have a “new” syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that
UBE3B
mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the
UBE3B
-associated phenotypes, including forms that can mimick Toriello–Carey syndrome, and suggest the single designation “Kaufman oculocerebrofacial syndrome”.
Disorders of cobalamin deficiency are a heterogeneous group of disorders with at least 19 autosomal recessive-associated genes. Familial samples of an infant who died due to presumed cobalamin ...deficiency were referred for clinical exome sequencing. The patient died before obtaining a blood sample or skin biopsy, autopsy was declined, and DNA yielded from the newborn screening blood spot was insufficient for diagnostic testing. Whole-exome sequencing of the mother, father, and unaffected sister and tailored bioinformatics analysis was applied to search for mutations in underlying disorders with recessive inheritance. This approach identified alterations within two genes, each of which was carried by one parent. The mother carried a missense alteration in the MTR gene (c.3518C>T; p.P1173L) which was absent in the father and the sister. The father carried a translational frameshift alteration in the LMBRD1 gene (c.1056delG; p.L352Lfs*18) which was absent in the mother and present in the heterozygous state in the sister. These mutations in the MTR (MIM# 156570) and LMBRD1 (MIM# 612625) genes have been described in patients with disorders of cobalamin metabolism complementation groups cblG and cblF, respectively. The child’s clinical presentation and biochemical results demonstrated overlap with both cblG and cblF. Sanger sequencing using DNA from the infant’s blood spot confirmed the inheritance of the two alterations in compound heterozygous form. We present the first example of exome sequencing leading to a diagnosis in the absence of the affected patient. Furthermore, the data support the possibility for potential digenic inheritance associated with cobalamin deficiency.
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