Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies.

Genome-scale high-throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population-based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal-dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co-occurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal-dominant disorders, enabling the estimation of variant-filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co-occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co-occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.

Exploring the potential association among sleep disturbances, cognitive impairments, and immune activation in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.DS) is a neurogenetic disorder caused by a microdeletion in chromosome 22. Its phenotype includes high rates of psychiatric disorders, immune system abnormalities, and cognitive impairments. We assessed the quality of sleep in 22q11.2DS and its potential link to inflammatory markers and cognitive deficits. Thirty-three 22q11.2DS individuals and 24 healthy controls were studied. Sleep parameters were assessed by the Pittsburgh sleep quality index (PSQI) questionnaire and correlated with serum cytokine levels and cognitive functioning, measured using the Penn computerized neurocognitive battery (CNB). The 22q11.2DS individuals had significantly worse sleep quality scores than the controls, unrelated to the psychiatric or physical comorbidities common to 22q11.2DS. Interleukin 6 levels were correlated with the overall score of the PSQI questionnaire for nonpsychotic 22q11.2DS participants only. Several domains of the CNB were associated with poorer sleep quality, suggesting that cognitive impairments in 22q11.2DS may be at least partially explained by poor sleep quality. Our findings confirm sleep impairments in individuals with 22q11.2DS, which might negatively affect their cognitive functioning, and corroborate a potential role of immunological pathways in the 22q11.2DS neuro-phenotype.

Non-pharmacological treatment of psychiatric disorders in individuals with 22q11.2 deletion syndrome; a systematic review.

22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of anxiety disorders, psychotic disorders, and other psychiatric conditions. In the general population, psychiatric disorders are treated with proven pharmacological and non-pharmacological therapies, such as cognitive behavioral therapy (CBT). To begin to assess the feasibility and efficacy of non-pharmacological therapies in 22q11.2DS, we performed a systematic search to identify literature on non-pharmacological interventions for psychiatric disorders in individuals with 22q11.2DS. Of 1,240 individual publications up to mid-2016 initially identified, 11 met inclusion criteria. There were five literature reviews, five publications reporting original research (two originating from a single study), and one publication not fitting either category that suggested adaptations to an intervention without providing scientific evidence. None of the original research involved direct study of the evidence-based non-pharmacological therapies available for psychiatric disorders. Rather, these four studies involved computer-based or group interventions aimed at improving neuropsychological deficits that may be associated with psychiatric disorders. Although the sample sizes were relatively small (maximum 28 participants in the intervention group), these reports documented the promising feasibility of these interventions, and improvements in domains of neuropsychological functioning, including working memory, attention, and social cognition. The results of this review underline the need for research into the feasibility and efficacy of non-pharmacological treatments of psychiatric disorders in individuals with 22q11.2DS to inform clinical care, using larger samples, and optimally, standard randomized, placebo-controlled, clinical trials methodology.

Craniosynostosis, Scheuermann's disease, and intellectual disability resembling Shprintzen-Goldberg syndrome: a report on a family over 4 generations: Case report.

RATIONALE: Craniosynostosis is a disorder characterized by premature fusion of cranial sutures with subsequent development of abnormal craniofacial contour associated with variable skeletal and extra-skeletal abnormalities. In this family syndromic type of craniosynostosis was recognized and the etiology behind diverse forms of deformities have been diagnosed. PATIENT CONCERNS: The negative impact of the disorder on the child and his family is enormous. Particularly when the diagnosis is late and little can be done. Though counselling the family through discussing the whole picture of the disorder might lessens their concern. DIAGNOSES: Diagnosis is the corner stone of management. In this paper we aimed to sensitize pediatricians, physicians, and orthopedic surgeons concerning the necessity to recognize syndromic associations early on. INTERVENTIONS: Patients with syndromic craniosynostosis are usually associated with a complexity of malformation complex. Craniofacial surgery can be of remarkable help if the diagnosis is made early. It requires a series of corrections to avoid intellectual disability and other neurological deficits.The timing of interventions is strongly correlated on the timing of diagnosis. OUTCOMES: The earliest the diagnoses, the much better the outcomes are. And consequently avert the psychological and the financial cost on the patient and his family. LESSONS: The golden principle of medicine should prevail in all medical disciplines, which states: The more you see, the more you know and conversely the more you know is the more you see.

Shprintzen-Goldberg syndrome: a rare disorder.

Shprintzen-Goldberg Syndrome is an extremely infrequent disorder of connective tissue, characterized by craniosynostosis and marfanoid features, also known as Marfanoid Craniosynostosis syndrome. The syndrome was first introduced by Sugarman and Vogel' (1981) however, Shprintzen and Goldberg established this as a separate clinical entity in the year 1982. Since then, approximately sixty such cases have been set down in writing in the medical literature. Herein, we present a short review of literature of this rare connective disorder, in order to create awareness about this condition, as the magnitude of this disorder is not measured properly due to the paucity of literature.

Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes.

Cardiovascular abnormalities are the major cause of morbidity and mortality in Marfan syndrome (MFS) and a few clinically related diseases that share, with MFS, the pathogenic contribution of dysregulated transforming growth factor ß (TGFß) signaling. They include Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome and syndromic thoracic aortic aneurysms. Unlike the causal association of MFS with mutations in an extracellular matrix protein (ECM), the aforementioned conditions are due to defects in components of the TGFß pathway. While TGFß antagonism is being considered as a potential new therapy for these heritable syndromes, several points still need to be clarified in relevant animal models before this strategy could be safely applied to patients. Among others, unresolved issues include whether elevated TGFß signaling is responsible for all MFS manifestations and is the common trigger of disease in MFS and related conditions. The scope of our review is to highlight the clinical and experimental findings that have forged our understanding of the natural history and molecular pathogenesis of cardiovascular manifestations in this group of syndromic conditions.

[Fiberoptic tracheal intubation through the supraglottic airway device air-Q in a patient with Shprintzen-Goldberg syndrome].

We report a case of successful fiberoptic tracheal intubation through the supraglottic airway device air-Q in a 14-year-old boy in whom intubation was difficult because of Shprintzen-Goldberg syndrome. Shprintzen-Goldberg syndrome is a rare congenital disorder of connective tissue. The patient showed dysmorphic facies and weakness of connective tissue, and was scheduled to undergo abdominal surgery. After induction of general anesthesia, both attempts of laryngoscope-guided and AirwayScope -guided tracheal intubation failed, but a size-2 air-Q could be easily inserted. Fiberoptic tracheal intubation through the air-Q was successfully performed without any difficulty and was safe for his weak airway connective tissue. Supraglottic airway air-Q is a useful conduit for fiberoptic tracheal intubation under general anesthesia, especially in the case of a patient with weak connective tissue in whom intubation is difficult.

Severe acute respiratory failure secondary to acute fibrinous and organizing pneumonia requiring mechanical ventilation: a case report and literature review.

A 27-year-old woman was admitted to our ICU with acute hypoxemic respiratory failure and criteria for ARDS. Despite an F(IO(2)) of 1.0 and a lung protective strategy, the patient died on day 15 without any improvement. The relatives gave consent for post-mortem analysis. The histopathologic study of the lung showed findings typical of an acute fibrinous and organizing pneumonia. Apropos of this case we performed a PubMed search. We found 13 articles, including a total of 29 patients. Acute fibrinous and organizing pneumonia is an unusual cause of acute lung injury. The diagnostic criterion is histopathologic. There is little information regarding the pathophysiology of this illness. Important questions remain regarding this disease, including predisposing factors and management. Patients who require mechanical ventilation have poor outcomes.

Congenital hydrocephalus in clinical practice: a genetic diagnostic approach.

Congenital hydrocephalus is a common and often disabling disorder. The etiology is very heterogeneous. Little is known about the genetic causes of congenital hydrocephalus. A retrospective survey was performed including patients with primary congenital hydrocephalus referred to the Department of Clinical Genetics between 1985 and 2010 by perinatologists, (child) neurologists or pediatricians. Patients with hydrocephalus secondary to other pathology were excluded from this survey. We classified patients with primary congenital hydrocephalus into two main groups: non-syndromic hydrocephalus (NSH) and syndromic hydrocephalus (SH). Seventy-five individuals met the inclusion criteria, comprising 36% (27/75) NSH and 64% (48/75) SH. In 11% (8/75) hydrocephalus was familial. The cause of hydrocephalus was unknown in 81% (61/75), including all patients with NSH. The male-female ratio in this subgroup was 2.6:1, indicating an X-linked factor other than the L1CAM gene. In the group of SH patients, 29% (14/48) had a known cause of hydrocephalus including chromosomal abnormalities, L1 syndrome, Marden-Walker syndrome, Walker-Warburg syndrome and hemifacial microsomia. We performed this survey in order to evaluate current knowledge on the genetic etiology of primary congenital hydrocephalus and to identify new candidate genes or regulatory pathways for congenital hydrocephalus. Recommendations were made concerning the evaluation and genetic workup of patients with primary congenital hydrocephalus. We conclude that further molecular and functional analysis is needed to identify new genetic forms of congenital hydrocephalus.

Surgical treatment for scoliosis in patients with Shprintzen-Goldberg syndrome.

BACKGROUND: Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis and marfanoid habitus. The clinical findings of SGS include neurological, cardiovascular, connective tissue, and skeletal abnormalities. Among these skeletal findings, developmental scoliosis is recognized in half of all patients with SGS. However, no earlier reports have described the surgical treatment of scoliosis associated with SGS. METHODS: Four patients (2 boys and 2 girls; mean age at the time of surgery, 7.3±4.4 y) with SGS who underwent surgical treatment for progressive scoliosis were reviewed. The radiologic findings, operative findings, and perioperative complications were evaluated. RESULTS: The mean preoperative Cobb angle was 102.8±16.9 degrees. The curve patterns were a double curve in 2 cases and a triple curve in 2 cases. Local kyphosis at the thoracolumbar area was recognized in all the cases with a mean kyphosis angle of 49±16 degrees. Growing rod procedures were performed in 2 patients, and posterior correction and fusion were performed in 2 patients. The mean correction rate was 45% in the patients who underwent the growing rod procedures at the time of growing rod placement and 51% in the patients who underwent posterior correction and fusion. Dislodgement of the proximal anchors occurred in 3 of the 4 patients. One patient developed pseudoarthrosis. Two patients developed deep wound infections, and implant removal was necessary in 1 patient. CONCLUSIONS: Surgical treatment for scoliosis in patients with SGS was associated with a high incidence of perioperative and postoperative complications including implant dislodgements and deep wound infections attributable to poor bone quality and a thin body habitus, which are characteristic clinical features of this syndrome. Careful preoperative surgical planning and postoperative care are critical for the surgical treatment of scoliosis associated with SGS, especially in infants requiring multiple surgeries. LEVEL OF EVIDENCE: Level IV.

Aracnodactilia contractural congénita / Congenital contractural arachnodactyly

La aracnodactilia contractural congénita (ACC) es un trastorno del tejido conectivo debido a una mutación autosómica dominante. La persona afectada de ACC presenta múltiples expresiones clínicas, incluidas las cardiacas y, principalmente, las musculoesqueléticas. Los progresos en el control de la gestación y la accesibilidad a técnicas de reproducción asistida llevan, cada vez más, a tener que atender situaciones como el caso clínico que se presenta: una gestación gemelar bicorial biamniótica obtenida por técnica de fertilización in vitro en una mujer afectada de dicha enfermedad. Los retos diagnósticos, las alternativas terapéuticas, el pronóstico materno y neonatal y las repercusiones sociales y éticas de estos casos son temas para la reflexión(AU)

Congenital contractural arachnodactyly (CCA) is a connective tissue disorder caused by an autosomal dominant mutation. Affected individuals show multiple involvement, including cardiac and, mainly, musculoskeletal abnormalities. Because of advances in pregnancy management and access to assisted reproduction techniques, situations such as that reported in the present article will become more frequent: we describe a dichorionic diamniotic twin gestation obtained by in vitro fertilization in a woman with CCA. The diagnostic challenges, therapeutic alternatives, maternal and neonatal outcomes, and the social and ethical repercussions of these cases are discussed(AU)