Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 ...pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon.
We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways.
Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00-27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05.
To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results.
X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has ...hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5-10% for X-chromosomal defects in male ID patients.
BackgroundFetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in ...many individuals. We aimed to further define the set of genes involved.MethodsWe performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature.ResultsWe identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene (KIF21A) was found.ConclusionOur study underlines the broad locus heterogeneity of FA with well-established and atypical genotype–phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets.
Background
Bi‐allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing ...loss. We report on a 6 1/2‐year‐old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly.
Methods
We performed trio exome sequencing on the patient and her parents.
Results
Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B c.527G>T, p.(Gly176Val) and c.1313T>C, p.(Leu438Pro) in the patient.
Conclusion
Of note, the change c.1313T>C, p.(Leu438Pro) has been observed in a previously published patient as part of a complex disease allele along with a second homozygous missense change, so the exact contribution of the two alterations to this patient's disease had initially remained unclear. Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient.
In a 6 1/2‐year‐old girl with a neurodevelopmental disorder, we identified compound heterozygous variants in AFG2B c.527G>T, p.(Gly176Val) and c.1313T>C, p.(Leu438Pro) by using trio exome sequencing. Our result support the pathogenic relevance of the variant c.1313T>C, p.(Leu438Pro), which had initially remained unclear in a previously described patient.
Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the
gene causing GDACCF syndrome (global ...developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far.
As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals.
The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the
gene. Heterozygous deletion including the entire
gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families.
The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with '
-related neurodevelopmental disorder'.
Multicystic encephalomalacia (ME) usually results from severe hypoxic-ischemic brain damage occurring during the late third trimester of gestation and birth. We report on a case of congenital ME due ...to a congenital anomaly of the aortic origin of brachiocephalic vessels resulting in subclavian steal syndrome. A 5-day-old term neonate presented with microcephaly and overlapping cranial sutures. Both arms were developed normally. Magnetic resonance imaging of the brain showed extensive bilateral supratentorial ME. Color duplex sonography of the aortic arch and the intracranial and extracranial vessels revealed a stenosis at the origin of the left common carotid artery and atresia of the origin of the left subclavian artery resulting in left-sided subclavian steal syndrome and retrograde perfusion of the basilar artery. Total cerebral blood flow volume was reduced to 22 mL/min. Severely reduced cerebral blood flow volume resulted from left carotid artery stenosis and atresia of the origin of the left subclavian artery with consecutive subclavian steal. Infratentorial brain structures and the left arm remained intact, but supratentorial brain structures were severely affected with ME.
To investigate prospectively the development of cerebral perfusion during infancy, serial quantitative measurements of cerebral blood flow (CBF) volume were performed in two healthy children from ...birth up to the age of 30 mo. A total of 28 CBF volume measurements were done in either of the children. Absolute flows were measured in the internal carotid and vertebral arteries on both sides. Blood flow was calculated as the product of angle-corrected time-averaged flow velocity and the cross-sectional area of the vessel. Starting from 67 and 80 mL/min, respectively, at birth an almost 10-fold increase of CBF volume was observed in both children during the examination period. Half of this rise occurred during the first 6 mo, probably reflecting the steep metabolic incline during this period of synaptogenesis. The continuous increase in CBF volume after the sixth month of life mainly corresponds to brain growth. Estimated CBF (based on estimated brain weights) increased from 21 and 23 mL 100 g(-1) min(-1), respectively, after birth to 46 and 53 mL 100 g(-1) min(-1), respectively, during the first 6 mo of life in both children, remaining stable thereafter. This study is the first to provide longitudinal data of CBF during the first 30 mo after birth.
Objectives
To examine the diagnostic yield of trio exome sequencing in fetuses with multiple structural defects with no pathogenic findings in cytogenetic and microarray analyses.
Methods
We ...recruited 51 fetuses with two or more defects, non‐immune fetal hydrops or fetal akinesia deformation syndrome|or fetal akinesia deformation sequence (FADS). Trio exome sequencing was performed on DNA from chorionic villi samples and parental blood. Detection of genomic variation and prioritization of clinically relevant variants was performed according to in‐house standard operating procedures.
Results
Median maternal and gestational age was 32.0 years and 21.0 weeks, respectively. Forty‐three (84.3%) fetuses had two or more affected organ systems. The remaining fetuses had isolated fetal hydrops or FADS. In total, the exome analysis established the genetic cause for the clinical abnormalities in 22 (43.1%, 95% CI 29.4%–57.8%) pregnancies.
Conclusions
In fetuses with multiple defects, hydrops or FADS and normal standard genetic results, trio exome sequencing has the potential to identify genetic anomalies in more than 40% of cases.
Key points
What's already known about this topic?
Genome‐wide sequencing for unspecific heterogeneous syndromic and non‐syndromic congenital conditions increases the diagnostic yield compared with standard genetic testing in both the pre‐ and postnatal settings. The diagnostic yield prenatally varies depending on selection criteria and number of anomalies present.
What does this study add?
Trio exome sequencing should be considered for fetuses with normal cytogenetic and micro‐array analysis and two or more organ defects, fetal hydrops or fetal akinesia syndromes. Selection of cases for exome sequencing should be based on expert prenatal imaging.
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