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PurposeDeep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30-40% of known genetic syndromes. Here, we determine whether syndromes can be diagnosed from 3D images of human faces.MethodsWe analyzed variation in three-dimensional (3D) facial images of 7057 subjects: 3327 with 396 different syndromes, 727 of their relatives, and 3003 unrelated, unaffected subjects. We developed and tested machine learning and parametric approaches to automated syndrome diagnosis using 3D facial images.ResultsUnrelated, unaffected subjects were correctly classified with 96% accuracy. Considering both syndromic and unrelated, unaffected subjects together, balanced accuracy was 73% and mean sensitivity 49%. Excluding unrelated, unaffected subjects substantially improved both balanced accuracy (78.1%) and sensitivity (56.9%) of syndrome diagnosis. The best predictors of classification accuracy were phenotypic severity and facial distinctiveness of syndromes. Surprisingly, unaffected relatives of syndromic subjects were frequently classified as syndromic, often to the syndrome of their affected relative.ConclusionDeep phenotyping by quantitative 3D facial imaging has considerable potential to facilitate syndrome diagnosis. Furthermore, 3D facial imaging of "unaffected" relatives may identify unrecognized cases or may reveal novel examples of semidominant inheritance.

The presence of multiple dysmorphic features in some children with autism spectrum disorder (ASD) might identify distinct ASD phenotypes and serve as potential markers for understanding causes and prognoses. To evaluate dysmorphology in ASD, children aged 3-6 years with ASD and non-ASD population controls (POP) from the Study to Explore Early Development were evaluated using a novel, systematic dysmorphology review approach. Separate analyses were conducted for non-Hispanic White, non-Hispanic Black, and Hispanic children. In each racial/ethnic group, ~ 17% of ASD cases were Dysmorphic compared with ~ 5% of POP controls. The ASD-POP differential was not explained by known genetic disorders or birth defects. In future epidemiologic studies, subgrouping ASD cases as Dysmorphic vs. Non-dysmorphic might help delineate risk factors for ASD.

Introduction: Penttinen premature aging syndrome is caused by mutations in the PDGFRB gene. We describe the case of a 10-year-old girl with a de novo c.1994T>C variant in PDGFRB who developed multiple cranial, intracranial, and spinal manifestations, including macrocephaly, enlarged convexity subarachnoid spaces crossed by numerous vascularized arachnoid trabecule, hydrocephalus, spinal epidural lipomatosis, a low conus medullaris, calvarial thinning with large anterior fontanelle, and a skull fracture with bilateral epidural hematomas. Vascularized arachnoid granulations, spinal epidural lipomatosis, and low conus medullaris have not been previously described in Penttinen syndrome. Case Presentation: A female with Penttinen syndrome diagnosed at 9 years of age initially presented as an infant with cutaneous hemangiomas and macrocephaly; imaging showed enlarged convexity subarachnoid spaces. Her convexity subarachnoid spaces continued to expand, leading to subdural shunt placement. At surgery, her enlarged subarachnoid spaces were found to contain numerous abnormally thick, vascularized arachnoid trabecule. Eventually, her subdural shunt failed and her ventricles enlarged, leading to ventricular shunt placement. A large, sunken anterior fontanelle which did not diminish in size led to cranioplasty with a custom implant. She later developed chronic back pain and imaging revealed spinal epidural lipomatosis, a low conus medullaris, and mild scoliosis. At 10 years of age, a fall from a chair resulted in a depressed skull fracture and bilateral parietal epidural hematomas. Emergency left parietal craniotomy was performed for evacuation of the left hematoma, and the patient recovered without complications. Intraoperatively, it was noted that her skull was extremely thin. Conclusion: This case report highlights the clinical presentation and multifaceted neurosurgical management of a patient with Penttinen syndrome. The patient exhibited characteristic features including hypertrophic skin lesions, macrocephaly, and skeletal abnormalities. Our patient's vascularized arachnoid trabecule, spinal epidural lipomatosis, and low conus medullaris have not previously been reported in Penttinen syndrome. Her thin skull potentially contributed to the extent of her depressed skull fracture after her backwards fall and predisposed her toward developing epidural hematomas. Patients with Penttinen syndrome can have multiple cranial, intracranial, and spinal manifestations which may need the attention of a neurosurgeon. [ABSTRACT FROM AUTHOR]

Skeletal dysplasias broadly include disorders of cartilage or bone. Omodysplasia‐1 is a type of skeletal dysplasia caused by biallelic loss of function variants in the GPC6 gene. GPC6 codes for the protein glypican 6 (GPC6) (OMIM *604404), which stimulates bone growth. We report a family in which five out of nine children were presented with a skeletal dysplasia characterized phenotypically by mild short stature and rhizomelia. All affected individuals were found to have homozygous missense variants in GPC6: c.511 C>T (p.Arg171Trp). Radiograph findings included rhizomelic foreshortening of all four extremities, coxa breva, and ulna minus deformity. Using a Hedgehog (Hh) reporter assay, we demonstrate that the variant found in this family results in significantly reduced stimulation of Hh activity when compared to the wild‐type GPC6 protein, however protein function is still present. Thus, the milder phenotype seen in the family presented is hypothesized due to decreased GPC6 protein activity versus complete loss of function as seen in omodysplasia‐1. Given the unique phenotype and molecular mechanism, we propose that this family's findings widen the phenotypic spectrum of GPC6‐related skeletal dysplasias. [ABSTRACT FROM AUTHOR]

Individuals with Down syndrome (DS) are diagnosed with autism spectrum disorder (ASD) at a significantly higher frequency than the typical population. The differentiation of ASD symptoms from those of severe intellectual disability presents diagnostic challenges, which have led to more refined methods in the clinical evaluation of ASD in DS. These improved phenotypic characterization methods not only provide better diagnosis of ASD in DS, but may also be useful in elucidating the etiology of the increased prevalence of ASD in DS. Because all individuals with the classic presentation of DS have trisomy 21, it is possible that those with co-occurring DS and ASD may have additional genetic variants which can act as modifiers of the phenotype, leading to the development of ASD. © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol biosynthesis associated with congenital malformations, growth delay, intellectual disability and behavior problems. SLOS is caused by bi-allelic mutations in DHCR7 , which lead to reduced activity of 7-dehydrocholesterol reductase that catalyzes the last step in cholesterol biosynthesis. Symptoms of SLOS are thought to be due to cholesterol deficiency and accumulation of its precursor 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC), and toxic oxysterols. Therapy for SLOS often includes dietary cholesterol supplementation, but lipids are poorly absorbed from the diet, possibly due to impaired bile acid synthesis. We hypothesized that bile acid supplementation with cholic acid would improve dietary cholesterol absorption and raise plasma cholesterol levels., Methods: Twelve SLOS subjects (10 M, 2F, ages 2-27 years) who had plasma cholesterol ≤125 mg/dL were treated with cholic acid (10 mg/kg/day) divided twice daily for 2 months. Plasma cholesterol, 7-DHC and 8-DHC were measured by GC-MS. Oxysterols were measured by ultra-high-performance LC-MS/MS. Data were analyzed using paired t -tests., Results: At baseline, plasma cholesterol was 75 ± 24 mg/dL (mean ± SD; range 43-125, n  = 12). After 2 months on cholic acid, mean plasma cholesterol increased to 97 ± 29 mg/dL ( p  = 0.011). Eleven of 12 subjects showed an increase in plasma cholesterol that varied from 3.8% to 85.7% (mean 38.7 ± 23.3%). 7-Hydroxycholesterol decreased by 20.6% on average ( p  = 0.013) but no significant changes were seen in 7-DHC or 8-DHC. Mean body weight tended to increase (3.6% p  = 0.069). Subjects tolerated cholic acid well and experienced no drug-related adverse events., Conclusions: In this pilot study, cholic acid supplementation was well tolerated and safe and resulted in an increase in plasma cholesterol in most SLOS subjects. Further controlled longitudinal studies are needed to look for the sustainability of the biochemical effect and possible clinical benefits., Competing Interests: None., (© 2023 Published by Elsevier Inc.)

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified Kdm5a as a candidate ASD gene. To validate our discovery, we generated a Kdm5a knockout mouse model ( Kdm5a -/- ) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a -/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome. To determine if KDM5A mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function., Competing Interests: LE, IT, NN, JR, SL, KK, XL, PA, MT, AG, AH, PZ, HA, AR, KH, MA, CW, BD, RL, MC, MF, RR, RA, EE, RM, HH, AL, BB, MC No competing interests declared, (© 2020, El Hayek et al.)

Restrictive cardiomyopathy (RCM) is a rare cause of heart muscle disease with the highest mortality rate among cardiomyopathy types. The etiology of RCM is poorly understood, although genetic causes have been implicated, and syndromic associations have been described. Here, we describe a patient with an atrial septal defect and restrictive cardiomyopathy along with craniofacial anomalies and intellectual disabilities. Initial screening using chromosomal microarray analysis (CMA) identified a maternally inherited 2q13 microdeletion. The patient had many of the features reported in previous cases with the recurrent 2q13 microdeletion syndrome. However, the inheritance of the microdeletion from an unaffected mother combined with the low incidence (10%) and milder forms of cardiac defects in previously reported cases made the clinical significance of the CMA results unclear. Whole-exome sequencing (WES) with trio-based analysis was performed and identified a paternally inherited TMEM87B mutation (c.1366A>G, p.Asn456Asp) in the patient. TMEM87B, a highly conserved, transmembrane protein of currently unknown function, lies within the critical region of the recurrent 2q13 microdeletion syndrome. Furthermore, a recent study had demonstrated that depletion of TMEM87B in zebrafish embryos affected cardiac development and led to cardiac hypoplasia. Thus, by combining CMA and WES, we potentially uncover an autosomal-recessive disorder characterized by a severe cardiac phenotype caused by mutations in TMEM87B. This study expands the spectrum of phenotypes associated with the recurrent 2q13 microdeletion syndrome and also further suggests the role of TMEM87B in its etiology, especially the cardiac pathology.