Search

Next-generation phenotyping (NGP) is an application of advanced methods of computer vision on medical imaging data such as portrait photos of individuals with rare disorders. NGP on portraits results in gestalt scores that can be used for the selection of appropriate genetic tests, and for the interpretation of the molecular data. Here, we report on an exceptional case of a young girl that was presented at the age of 8 and 15 and enrolled in NGP diagnostics on the latter occasion. The girl had clinical features associated with Koolen-de Vries syndrome (KdVS) and a suggestive facial gestalt. However, chromosomal microarray (CMA), Sanger sequencing, multiplex ligation-dependent probe analysis (MLPA), and trio exome sequencing remained inconclusive. Based on the highly indicative gestalt score for KdVS, the decision was made to perform genome sequencing to also evaluate noncoding variants. This analysis revealed a 4.7 kb de novo deletion partially affecting intron 6 and exon 7 of the KANSL1 gene. This is the smallest reported structural variant to date for this phenotype. The case illustrates how NGP can be integrated into the iterative diagnostic process of test selection and interpretation of sequencing results., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainly-causative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was observed regarding short stature with 5 versus 35%, respectively. However, these differences were nominally significant only after correction for multiple testing, further supporting the hypothesis that MYT1L haploinsufficiency is central to the 2p25.3 deletion phenotype. Most importantly, the large number of individuals with MYT1L mutations presented and reviewed here allowed for the delineation of a more comprehensive clinical picture. Seizures, postnatal short stature, macrocephaly, and microcephaly could be shown to be over-represented among individuals with MYT1L mutations., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)

Intellectual disability (ID) has an estimated prevalence of 1.5-2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.

We report on a high-power mid-infrared (MIR) frequency comb source based on a femtosecond (fs) Er:fiber oscillator with a stabilized repetition rate of 250 MHz. The MIR frequency comb is produced through difference frequency generation in a periodically poled MgO-doped lithium niobate crystal. The output power is about 120 mW, with a pulse duration of about 80 fs and spectrum coverage from 2.9 to 3.6 μm, and the single comb mode power is larger than 0.3 μW over the range of 700 nm. The coherence properties of the produced high-power broadband MIR frequency comb are maintained, which was verified by heterodyne measurements. As the first application, the spectrum of a ~200 ppm methane-air mixture in a short 20 cm glass cell at ambient atmospheric pressure and temperature was measured.

We report on the generation of wave breaking-free pulses from a passively mode-locked all-fiber Erbium oscillator at 1.55 microm pumped by a Raman fiber assembly operating at 1.48 microm. The extracted pulses show a self-similar behaviour and can be scaled up to an average power of 675 mW only limited by the pump power. The laser operates at the fundamental repetition rate of 108 MHz, therefore the pulse energy is 6.2 nJ. After external compression, the dechirped pulse duration is 64 fs.

We present a sub-85 fs self-starting stretched-pulse passively mode-locked Erbium-fiber oscillator in a sigma setup with tunable repetition rate. The sigma cavity included a movable mirror enabling a tunable pulse repetition rate variation of +/- 1 % from 55.3 MHz to 56.4 MHz with continuous, uninterrupted mode-locked operation and an output power around 14 mW. Based on the wide tuning range of the repetition rate the presented fiber oscillator is a suitable candidate for applications in femtosecond spectroscopy or precision metrology around 1.56 microm.

We report on the measurement of an Erbium-fiber oscillator's carrier-envelope-offset frequency using an extruded SF6 photonic crystal fiber for the generation of a more than two octave-spanning supercontinuum from 400 nm to beyond 1750 nm. A modified type of f-2f-interferometer was employed, beating the frequency doubled input signal of the fiber oscillator with the supercontinuum to generate the carrier-envelope-offset beat. Controlling the fiber oscillator's pump power with an electronic feedback loop, we phase-locked the carrier-envelope-offset frequency to an external reference source. The resulting residual phase excursions correspond to fractional frequency instabilities of the oscillator's frequency comb of the order of 10(-16) for averaging times longer than 10 s.

We report an all-fiber diode-pumped Erbium-fiber oscillator-amplifier system as a source for supercontinuum generation in a photonic crystal fiber at 1560 nm. The passively mode-locked oscillator-amplifier system provides linearly polarized output pulses of 60 fs and an average output power of 59 mW at a repetition rate of 59.1 MHz. The laser pulses were launched into an extruded SF6-fiber for generation of an ultra-broadband supercontinuum. The evolution of the supercontinuum as a function of launched pulse energy was investigated. With pulse energies of about 200 pJ we observed a more than octave-spanning supercontinuum from 400 nm to beyond 1750 nm.

In order to determine the birth risk for pregnant women in the age group > or = 40, the delivery data of 143 pregnant women in this age group were retrospectively evaluated over a 3-year period. Here, 37 of these 143 women (25.9%) were primiparae. The following was examined: The number of prenatal examinations (including ultrasound examinations), the incidence of genetic examinations, the delivery methods with the percentage of surgical deliveries, complications at the time of delivery as well as the fetal outcome with APGAR values, umbilical artery pH, birth weights, neonatal morbidity and mortality. The delivery results were compared with representative populations of women between 20-29 years (n = 2252) and 30-39 years (n = 1980). Pregnancy in older women still ends significantly more often with cesarean section than in younger women. Here, the rate of cesarean sections was 32.7% compared to 21.9% in 30-39-year-olds and 15.8% in 20-29-year-olds. However, parity has an even greater influence on the mode of delivery than age. Only 30.1% of multi-parae over 40 years underwent surgical delivery (vaginal and abdominal) compared to 77.3% of primiparae. It was also found that multiparae more rarely had surgical delivery than younger primiparae (30-39 years 53.3%, 20-29 years 39.3%). Despite the high surgical delivery rate being in the group of primiparae over 40 years, the fetal outcome was comparatively poor, so that the less restrictive indication for surgical delivery seems justified.