Despite increasing knowledge of disease-causing genes in human genetics, approximately half of the individuals affected by neurodevelopmental disorders remain genetically undiagnosed. Part of this missing heritability might be caused by genetic variants outside of protein-coding genes, which are not routinely diagnostically investigated. A recent preprint identified de novo variants in the non-coding spliceosomal snRNA gene RNU4-2 as a cause of a frequent novel syndromic neurodevelopmental disorder. Here we mined 164 whole genome sequencing (WGS) trios from individuals with neurodevelopmental or multiple congenital anomaly disorders that received diagnostic genomic investigations at our clinic. We identify a recurrent de novo RNU4-2 variant (NR_003137.2(RNU4-2):n.64_65insT) in a 5-year-old girl with severe global developmental delay, hypotonia, microcephaly, and seizures that likely explains her phenotype, given that extensive previous genetic investigations failed to identify an alternative cause. We present detailed phenotyping of the individual obtained during a 5-year follow-up. This includes photographs showing recognizable facial features for this novel disorder, which might allow prioritizing other currently unexplained affected individuals sharing similar facial features for targeted investigations of RNU4-2. This case illustrates the power of re-analysis to solve previously unexplained cases even when a diagnostic genome remains negative.

Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly; and dysmorphic features closely resembling those seen in trichorhinophalangeal syndrome (TRPS). These features include sparse hair, sparse lateral eyebrows, a bulbous pear shaped nose, a long philtrum, thin lips, small/hypoplastic nails, pes planovalgus; bilateral cone-shaped epiphyses at the proximal 5th phalanx, slender long bones, coxa valga, mild scoliosis, and delayed bone age. Given that TRPS had been excluded by a thorough genetic analysis, whole exome sequencing was performed and a heterozygous likely pathogenic variant was identified in the FBXO11 gene (NM_001190274.2: c.1781A > G; p. His594Arg), confirming the diagnosis of the newly individualized IDDFBA syndrome: Intellectual Developmental Disorder, dysmorphic Facies, and Behavioral Abnormalities (OMIM# 618,089). Our findings further delineate the clinical spectrum linked to FBXO11 and highlight the importance of investigating further cases with mutations in this gene to establish a potential genotype-phenotype correlation.

OBJECTIVE: To analyze the fertilization, developmental, and pregnancy potentials in oocytes with narrow perivitelline space.
METHODS: Perivitelline space (PVS) of oocytes was evaluated at the time of ICSI, and those without sufficient PVS were judged as oocytes with narrow PVS (NPVS oocytes), and those with sufficient PVS formation were judged as oocytes with non-narrow PVS (non-NPVS oocytes). The analysis included 634 NPVS oocytes from 278 cycles and 12,121 non-NPVS oocytes from 1698 cycles. The fertilization and developmental potentials of NPVS and non-NPVS oocytes were compared by calculating odds ratios using a mixed-effects logistic regression model. We also compared the embryo transfer outcomes of those used for single vitrified-warmed blastocyst transfer after developing into the blastocyst stage.
RESULTS: NPVS oocytes had higher odds ratios for degeneration (adjusted odds ratio [aOR], 1.555; 95% confidence interval [CI], 1.096-2.206; p = 0.0133) and 0PN (aOR, 1.387; 95% CI, 1.083-1.775; p = 0.0095), resulting in a lower 2PN rate (aOR, 0.761; 95% CI, 0.623-0.929; p = 0.0072). Even embryos with confirmed 2PN had lower odds ratios for cleavage (aOR, 0.501; 95% CI, 0.294-0.853; p = 0.0109) and blastocyst development (Gardner criteria; CC-AA) rates (aOR, 0.612; 95% CI, 0.476-0.788; p = 0.0001). Blastocysts developed from NPVS oocytes had significantly lower odds ratios for clinical pregnancy (aOR, 0.435; 95% CI, 0.222-0.854; p = 0.0156) than those developed from non-NPVS oocytes.
CONCLUSIONS: Oocytes with NPVS have low fertilization and developmental potential, as well as low likelihood of pregnancy.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.

OBJECTIVE: The diagnoses included within the umbrella term fetal alcohol spectrum disorders (FASD), are based on the documentation of prenatal alcohol exposure (PAE), growth deficits and a pattern of dysmorphic physical features and neurobehavioral impairments. Although 3 key facial features (short palpebral fissures, a smooth philtrum and a thin vermilion of the upper lip) are the only dysmorphic features taken into account for the diagnosis of Fetal Alcohol Syndrome (FAS) or partial FAS (pFAS), several other features are commonly seen in individuals with these diagnoses. The goals of our study were to determine if some of these secondary physical features also occur more frequently in children with alcohol-related neurodevelopmental disorder (ARND) relative to controls, and if a cluster of these features combined in a dysmorphology score could be used to identify those negatively impacted by PAE but who do not have the cardinal physical features that led to a diagnosis of FAS or pFAS.
METHODS: Among 2681 children recruited for the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence (CoFASP) study, 1726 had an FASD or sufficient evidence of PAE having occurred or not in their pregnancy. Children were then categorized into groups using the modified Hoyme diagnostic criteria (FAS (n = 24), pFAS (n = 99) and ARND (n = 87), and No FASD (n = 1516), including those with No FASD and a history of PAE (No FASD/PAE, n = 498) and those with No FASD and no history of PAE (No FASD/No PAE, n = 1018). The frequencies of 26 secondary dysmorphic features were compared among these groups, both individually and combined in non-weighted and weighted dysmorphic scores. Correlations of the total dysmorphic scores with an index of overall cognitive ability were also compared by group status.
RESULTS: Several of these features were significantly more frequent in children with FAS than in those with No FASD diagnosis with or without PAE but not in comparison to those with ARND. The number of features was also significantly higher in the FAS group as compared to all other groups for both weighted and unweighted dysmorphology scores but were not higher in the group with ARND when compared to the groups with No FASD either in the presence or absence of PAE. Although not diagnostic, higher total dysmorphology scores were predictive of lower general cognitive abilities in the group with ARND, suggesting severity of alcohol-related dysmorphology is predictive of severity of alcohol-related neurobehavioral impairment.
CONCLUSIONS: Secondary physical features were not more frequent in children with ARND compared to children without an FASD diagnosis but were a marker for lower cognitive function. The use of secondary physical features to support a diagnosis of ARND was not supported in this sample.

Neurodevelopmental disorders exhibit recurrent facial features that can suggest the genetic diagnosis at a glance, but recognizing subtle dysmorphisms is a specialized skill that requires very long training. Face2Gene (FDNA Inc) is an innovative computer-aided phenotyping tool that analyses patient\'s portraits and suggests 30 candidate syndromes with similar morphology in a prioritized list. We hypothesized that the software could support even expert physicians in the diagnostic workup of genetic conditions. In this study, we assessed the performance of Face2Gene in an Italian dysmorphological pediatrics clinic. We uploaded two-dimensional face pictures of 145 children affected by genetic conditions with typical phenotypic traits. All diagnoses were previously confirmed by cytogenetic or molecular tests. Overall, the software\'s differential included the correct syndrome in most cases (98%). We evaluated the efficiency of the algorithm even considering the rareness of the genetic conditions. All \"common\" diagnoses were correctly identified, most of them with high diagnostic accuracy (93% in top-3 matches). Finally, the performance for the most common pediatric syndromes was calculated. Face2Gene performed well even for ultra-rare genetic conditions (75% within top-3 matches and 83% within top-10 matches). Expert geneticists maybe do not need computer support to recognize common syndromes, but our results prove that the tool can be useful not only for general pediatricians but also in dysmorphological clinics for ultra-rare genetic conditions.

Caseinolytic peptidase B homolog (CLPB) is a mitochondrial protein which is highly expressed in brain. Its deficiency may be associated with severe neonatal encephalopathy. This report describes a case of fatal neonatal encephalopathy associated with biallelic stop-gain mutation in CLPB (NM_001258392.3:c.1159C>T/p.Arg387*). Neurologic disorder encompasses pre- and post-natal features including polyhydramnios, intrauterine growth restriction, respiratory insufficiency, lethargy, excessive startle reflex, generalized hypertonia, and epileptic seizures. Brain macroscopic examination demonstrates frontal severe periventricular cystic leukoencephalopathy, along with mild ex-vacuo tri-ventricular dilatation. The most striking immunohistopathologic features are striato-thalamic neurodegeneration and deep white matter loss associated with strong reactive astrogliosis. This report supports that CLPB deficiency should be considered among the neurometabolic disorders associated with severe prenatal-onset neurologic impairment that may result from cystic leukoencephalopathy.

UNASSIGNED: Skeletal growth arrest lines (GAL) are transverse lines of metaphyseal radiodensity accompanying episodic severe physiological stress. They are poorly described in fetal remains.
UNASSIGNED: We searched our autopsy practice for instances of fetal GAL in post mortem radiology, and correlated them with long bone histology and placental pathology. We describe the appearance, distribution, and pathology of GAL in a cohort of fetal autopsies, and compare the placental pathology accompanying GAL to the placental pathology of asymmetrical growth restriction (AGR) in the same time period.
UNASSIGNED: In 2108 consecutive fetal post mortems, we found 20 cases with GAL. About 16 were in singletons with AGR. In these 16, the distribution of placental pathologies was similar to a contemporaneous cohort of 113 cases with AGR. Of the remaining 4, two twins out of 9 sets of monochorionic twins with AGR demonstrated GAL. One case of GAL had symmetrical growth restriction with cytomegalovirus infection, and one case had no AGR and an old, unexplained retroplacental hemorrhage. On histology, GAL are characterized by a region of mineralized chondroid, which is variably incorporated into irregular trabecular bone.
UNASSIGNED: GALs accompany a variety of placental pathologies and twin-twin transfusion, suggesting episodic disease progression.

OBJECTIVE: The objective of this study was to develop a simple tool for general physicians to promptly identify and refer pediatric patients with a higher probability of having a genetic condition.
METHODS: This retrospective, descriptive study was conducted at a tertiary pediatric hospital\'s Clinical Genetics Unit from June 2019 to January 2020. We included patients under 18 years of age who visited the unit, excluding those without genetic testing. Epidemiological, clinical, and genetic variables were collected from electronic medical records. The primary outcome was the diagnosis of a genetic condition based on genetic testing.
RESULTS: Among 445 patients, 304 were included; 163 (53.6%) were male, and mean age was 7.4 years (SD 5.1 years). A genetic condition was diagnosed in 139 patients (45.7%). Using a multiple logistic regression model, five variables significantly contributed to reaching a diagnosis: suspected diagnosis at referral (OR 3.45, P < 0.001), short stature (OR 3.11, P < 0.001), global developmental delay/intellectual disability (OR 2.65, P < 0.001), dysmorphic craniofacial features (OR 1.99, P = 0.035), and multiple congenital anomalies (OR 2.54, P = 0.033). The association strength (OR) increased when these variables were paired with each other. The study\'s findings are presented in the form of a triangle, known as the Clinical Genetics Assessment Triangle (CGAT), which summarizes the results. A decision tree model is applied to guide clinical department referrals based on the affected sides of the triangle.
CONCLUSIONS: The CGAT has the potential to enable general physicians to promptly identify pediatric patients with an increased probability of having a genetic condition.

Family history and physical exam findings are often the first clues that prompt medical providers to consider clinical genetics evaluation. There is standardized nomenclature for both the pedigree and description of physical features. Systematic evaluation of patients through obtaining family history and careful physical examination is essential to the formulation of a differential diagnosis and plan in the clinical genetics evaluation. The goal of this article is to provide an overview of family history and dysmorphology exam, and their relevance for the clinical genetics evaluation.