MED13 Gene Mutation Related to Autism Spectrum Disorder: A Case Report.

This case report highlights an association between the MED13 gene and autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by impaired social interactions, communication difficulties, and repetitive behaviors. The MED13 gene encodes a subunit of the Mediator complex, which plays a key role in gene expression regulation and transcriptional processes. In this case report, we present a case of a child diagnosed with ASD who underwent whole exome sequencing (WES) and revealed an uncertain heterozygous variant in the MED13 gene. The patient exhibited typical features of ASD, including the following: social and communication deficits, restricted interests, repetitive behaviors, and characteristic dysmorphic facial features. The identification of this MED13 gene variant provides further evidence of its potential involvement in ASD pathogenesis. This case adds to the growing body of evidence linking MED13 gene mutations to ASD susceptibility. Understanding the genetic basis of ASD through case reports can aid in early diagnosis, personalized treatment strategies, and genetic counseling for affected individuals and their families. Further research is warranted to explain the precise mechanisms underlying MED13 gene involvement in ASD.

Long-Term Follow-up of Untreated Adult Patients with Spondylothoracic Dysostosis (Jarcho-Levin Syndrome).

BACKGROUND: Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is a rare autosomal recessive disorder affecting the formation of the spine, characterized by a complete bilateral fusion of the ribs at the costovertebral junction, producing a "crablike" appearance of the thorax. Despite being declared a core indication for a V-osteotomy vertical expandable prosthetic titanium rib (VEPTR) expansion thoracoplasty of the posterior thorax, the natural history of STD in untreated subjects remains poorly documented. In this study, we report radiographic and pulmonary function findings and Patient-Reported Outcomes Measurement Information System (PROMIS) and 24-Item Early Onset Scoliosis Questionnaire (EOSQ-24) scores for untreated adult subjects with STD to gain insights into the natural history. METHODS: We identified 11 skeletally mature, untreated subjects with STD. Findings on medical evaluation, demographics, radiographic parameters, pulmonary function, genetic testing results, PROMIS measures, and EOSQ-24 scores were assessed. RESULTS: Five male and 6 female subjects (mean age, 32.3 years [range, 15 to 70 years]) with a confirmed STD diagnosis based on radiographs and genetic testing were evaluated. Mean body mass index (BMI) was 24.4 kg/m 2 (range, 18 to 38.9 kg/m 2 ), and mean thoracic height was 16 cm (range, 12 to 17 cm). Pulmonary function tests (PFTs) showed a mean forced vital capacity (FVC) of 22% of predicted, mean forced expiratory volume in 1 second (FEV1) of 24% of predicted, and FEV1/FVC ratio of 107% of predicted. The mean PROMIS dyspnea score was 40 ± 8 points (range, 27.7 to 52.1 points). The mean total EOSQ-24 score was 77.3 ± 18 points (range, 43.9 to 93.2 points). CONCLUSIONS: Our study characterizes the natural history of STD in untreated subjects. We confirmed the expected restrictive pattern in pulmonary function, but interestingly, our subjects exhibited better EOSQ scores compared with those reported in neuromuscular populations. PFT results and thoracic height did not correspond to PROMIS and EOSQ scores, questioning the use of those parameters as a surgical indication. We therefore suggest that the STD diagnosis as an absolute indication for VEPTR expansion thoracoplasty surgery be reconsidered. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Homozygous TRPV4 Mutation Broadens the Phenotypic Spectrum of Congenital Spinal Muscular Atrophy and Arthrogryposis: A Case Report.

Transient receptor potential vanilloid 4 (TRPV4) mutations are known to cause inherited axonal neuropathies and skeletal dysplasia. TRPV4 mutations are associated with distal hereditary motor neuropathies (dHMN), which distinctly involve motor deficits. A 1 ½-year-old boy presented at the clinic with diminished lower limb movement and ambulatory limitations. The patient was born with bilateral knee arthrogryposis and bilateral talipes equinovarus, which required surgical intervention. A gross neurologic exam was unremarkable, with normal vision and hearing. A bone survey radiograph showed no evidence of skeletal dysplasia. Genetic tests revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L), leading to the diagnosis of congenital spinal muscular atrophy and arthrogryposis (CSMAA). Hence, this presents the first case of CSMAA caused by a TRPV4 mutation (p.S94L), with a different presentation from the one previously described in the literature, thus broadening the phenotypic variability and clinical spectrum of TRPV4 mutations.

Pathogenic Presentation of a Variant of Uncertain Significance in a Puerto Rican Patient With Wiedemann-Steiner Syndrome.

Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder that is caused by mutations in the KMT2A gene. This case reports a two-year-old male's diagnosis of WDSTS via a heterozygous variant of uncertain significance (VUS) (c.11735G>A(p.Cys3912Tyr). The patient's phenotypic presentation was remarkable for hypertrichosis, intellectual disability, intermittent aggressive behavior, developmental delay, failure to thrive, low weight, and the distinct facial features of long eyelashes, telecanthus, corrected strabismus, down-slanting palpebral fissures, and a wide nasal bridge with a broad tip. The importance of this case report stands on the principle of genetic evaluation in patients with ambiguous clinical presentations. In the future, molecular analysis of VUS with pathogenic clinical features can lead to targeted medical management and counseling.

COL1A2 (p.Gly322Ser) Mutation Causes Late-Onset Osteogenesis Imperfecta: A Case Report.

Osteogenesis imperfecta (OI) is a genetically inherited disorder that mainly affects the bones and causes a generalized decrease in bone mass. OI has a broad clinical spectrum ranging from the most severe form of OI which may cause in-utero death or stillbirth to the milder form. Clinical manifestations normally mitigate with an increase in age. We report a case of a healthy 12-year-old male who presented with a spontaneous fracture of the femur without trauma. The patient has no previous history of fractures, bone deformities or systemic conditions. The initial physical examination was unremarkable except for a bilateral subtle grayish sclera. Calcium, phosphorus, vitamin D, blood urea nitrogen (BUN), creatinine, and parathyroid hormone (PTH) values were within normal range. After genetic testing, the patient was diagnosed with OI due to a pathogenic COL1A2 (c.964G>A [p.Gly322Ser]) mutation. The first manifestation was at 12 years of age with a femur spontaneous fracture, which brings to the fact that the patient has a late onset of OI.

Genetic Evaluation of Late-Onset Hypertrophic Cardiomyopathy: An Autobiographical Case Report.

Cardiomyopathy, also known as a pathology with a cardiovascular cause, can be further differentiated into multiple categories including genetic. Strong correlations between genetic mutations in sarcomeric proteins and presentation of cardiomyopathies have been made. This case report describes the clinical diagnosis of my late-onset hypertrophic cardiomyopathy, which was brought upon by symptoms of chest pain and palpitations that started approximately two years ago and had mostly gone unnoticed during this period. As a geneticist, I decided to undergo genetic test upon diagnosis. These tests found a heterozygous variant of uncertain significance (VUS) in the ALPK3 gene, c.399dup (p.Gly134ArgfsTer30), and a heterozygous c.7552G>A (p.Val2518Ile) VUS in the desmoplakin (DSP) gene. This autobiographical case report hopes to shed light on the importance of genetic screening in the search for the etiology of clinical symptoms.

Multiple de novo gene variations in a progeroid phenotype case report: haploinsufficiency mechanisms.

We are presenting the case of a 6-year-old male patient with progeroid phenotype and severe developmental delay referred to Genetic clinic. Given the complex phenotype an extensive metabolic and genetic evaluation was performed including a whole exome sequencing analysis that showed genetic variants in TTR, RELN, MYH6, PHIP, and SYNE2 genes. Patients' mother and brother were analyzed for the genetic variants in MYH6, PHIP and RELN. Both had same variants on PHIP and RELN as our patient, with no apparent phenotypical consequences. Physical examination was remarkable for dysmorphism including plagiocephaly, low set and abnormally shaped ears, up slanted palpebral fissures, hypoplastic alae nasi, and a head circumference two standard deviations below the 3rd percentile (microcephaly). Other characteristics include wrinkled skin, a broad forehead, sparse eyelashes in lower eyelid, short palpebral fissures, upturned nares, thick lips, right occipital plagiocephaly, overfolded helix and prominent anti-helix, protuberant chest, scaphoid abdomen, digitalized thumbs, and kyphosis due to low muscle tone. The patient presented abnormal EEG with evidence of epileptic discharges. A temporal bone CT showed plagiocephaly with flattening of the right occipital bone. Brain MRI showed callosal agenesis with bilateral colpocephaly with temporal horn dilatation, parahippocampal atrophy, lissencephaly and midbrain hypoplasia. The combination of de novo gene variants mentioned above has never been reported nor correlated as the result of haploinsufficiency mechanisms. Thus, we propose haploinsufficiency and loss of heterozygosity as etiological reasons for this patient phenotype. Further proteomic studies are needed to allocate the extense of genetic influence within the clinical manifestations.

Rapid-Onset Obesity Due to Impulsive Food-Seeking Behavior in a Puerto Rican Child With CHRNA7 15q13.3 Microdeletion.

A microdeletion in the 15q13.3 locus is an exceedingly rare condition affecting the CHRNA7 gene. There have been 11 pediatric cases of this mutation reported worldwide. Clinical characteristics of the 15q13.3 microdeletion are rapid-onset obesity, hypotonia, autism, seizures, congenital cardiac defects, and neuropsychiatric disorders including impulsive hyperphagia. We describe the case of a four-year-old female with CHRNA7 15q13.3 microdeletion presenting with morbid obesity due to impulsive food-seeking behavior. We have also conducted a literature review on 15q13.3 microdeletion and compared the clinical features with other rapid-onset obesity disorders in the pediatric population. The goal of this case report is to increase awareness concerning CHRNA7 15q13.3 microdeletion as part of the differential diagnosis of rapid-onset obesity associated with neuropsychiatric disorders in pediatrics.

9q34 & 16p13 chromosome duplications in autism.

Epigenetic mechanisms, genetic factors, and environment influence the diversity of phenotypes developed in various diseases. Duplications in several chromosomes are well characterized in the scientific literature, but partial duplications, in some cases, present with milder forms of a disease and are yet to be understood. Fortunately, the identification of genetic diseases has now become more feasible due to several cytogenetic techniques such as microarray analysis and karyotyping. With these tools, together with other laboratory results and clinical examination, we are able to report the first case in the medical literature of double partial trisomy of chromosome 9q34 and 16p13.

Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

Vitamin D levels and fracture risk among Hispanic children.

PURPOSE: There is a lack of knowledge about whether low vitamin D levels increase the risk of pediatric low-energy fractures among Hispanic population. The objective of this study is to determine whether there is a direct relationship between low vitamin D levels and the incidence of low-energy fractures in Hispanic children. METHOD: Cases included all consecutive patients evaluated with low-energy fractures in the pediatric orthopedic clinic. The control group consisted of all pediatric patients evaluated, without fractures, who had bone and joint pain complaints in the general pediatric clinic. The main focus was to compare cases and controls in relation to their vitamin D levels. Cases and controls were compared using t tests for means of quantitative variables and Chi-square tests. RESULTS: A total of 201 subjects, distributed as cases (n = 107) and controls (n = 94), were included in this study. One hundred twelve (55.7%) of the total study population were males. The mean age for the study population was 8.6 years old ranging from 1 year to 18 years, and standard deviation = 4.0 years. The median age for the study population was 9 years. The mean vitamin D level for the cases was 32.6 ng/dl (SD = 10.9); the mean vitamin D level for controls was 32.3 ng/dl (SD = 13.4). This difference was not statistically significant (t = 0.18, 95% CI - 3.2 to 3.9; p = 0.854). CONCLUSION: A direct relationship between low vitamin D levels and fracture risk in a Hispanic pediatric population was not established. LEVELS OF EVIDENCE: III.

A Phase II, Randomized, Safety and Immunogenicity Trial of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Children and Adults Living in Puerto Rico.

This was a double-blind, randomized, controlled, phase II clinical trial, two dose study of re-derived, live-attenuated, tetravalent dengue virus (TDEN) vaccine (two formulations) or placebo in subjects 1-50 years of age. Among the 636 subjects enrolled, 331 (52%) were primed, that is, baseline seropositive to at least one dengue virus (DENV) type. Baseline seropositivity prevalence increased with age (10% [< 2 years], 26% [2-4 years], 60% [5-20 years], and 93% [21-50 years]). Safety profiles of TDEN vaccines were similar to placebo regardless of priming status. No vaccine-related serious adverse events (SAEs) were reported. Among unprimed subjects, immunogenicity (geometric mean antibody titers [GMT] and seropositivity rates) for each DENV increased substantially in both TDEN vaccine groups with at least 74.6% seropositive for four DENV types. The TDEN vaccine candidate showed an acceptable safety and immunogenicity profile in children and adults ranging from 1 to 50 years of age, regardless of priming status. ClinicalTrials.gov: NCT00468858.

Exacerbation of mood symptoms associated to primary and secondary carnitine deficiency: a case report.

Rarely screened in psychiatric patients, primary and/or secondary Carnitine deficiency could be influencing and/or mimicking the mood symptoms of our patient population. The brain and specifically neurons are highly vulnerable to impairments in oxidative metabolism, which can lead to neuronal cell death and disorders of neurotransmitters causing changes in cognition and behavior. For this reason, identification of this disorder is important since its treatment could result in symptom improvement and better quality of life of our patients. We present a case where exacerbation of mood symptoms was associated to primary and secondary Carnitine deficiency.

Musculoskeletal manifestations of neonatal nonketotic hyperglycinemia.

PURPOSE: Neonatal nonketotic hyperglycinemia is an autosomal recessive inborn disorder of glycine metabolism in which large quantities of glycine accumulate in all body tissues. It is characterized by a progressive lethargy, hypotonia, myoclonic jerks, and early death secondary to respiratory problems. As a result of early diagnosis and treatment protocols, more patients survive the critical neonatal period with profound mental retardation, delayed developmental milestones, seizures, and spasticity. There are no reports about the orthopaedic manifestations of neonatal nonketotic hyperglycinemia. The purpose of this study is to evaluate the musculoskeletal findings of neonatal nonketotic hyperglycinemia. METHODS: This is a retrospective IRB-approved study of all patients in our Orthopaedic and Genetics Clinics with the diagnosis of neonatal nonketotic hyperglycinemia during a 10-year period. Demographic, clinical, and imaging data were analyzed. RESULTS: Twelve patients with neonatal nonketotic hyperglycinemia were evaluated, with a mean age of 7 years and 2 months (range: 5 months to 21 years). Seven were male and five were female. Eleven patients (92 %) have evidence of progressive early-onset neuromuscular scoliosis with a mean Cobb angle of 55° (range: 30-95°). Five children (42 %) presented evidence of progressive hip dislocation secondary to spasticity. All the patients have severe multiple joint contractures. CONCLUSION: Neonatal nonketotic hyperglycinemia is a rare metabolic disorder presented in the past as a lethal condition. Recent advances in early diagnosis and neonatal care improve overall outcome. As pediatric orthopaedic surgeons, we need to establish treatment based on update information of the disease and probability to improve quality of life.

Steel syndrome: dislocated hips and radial heads, carpal coalition, scoliosis, short stature, and characteristic facial features.

BACKGROUND: A syndrome of children with short stature, bilateral hip dislocations, radial head dislocations, carpal coalitions, scoliosis, and cavus feet in Puerto Rican children, was reported by Steel et al in 1993. The syndrome was described as a unique entity with dismal results after conventional treatment of dislocated hips. The purpose of this study is to reevaluate this patient population with a longer follow-up and delineate the clinical and radiologic features, treatment outcomes, and the genetic characteristics. METHODS: This is a retrospective cohort study of 32 patients in whom we evaluated the clinical, imaging data, and genetic characteristics. We compare the findings and quality of life in patients with this syndrome who have had attempts at reduction of the hips versus those who did not have the treatment. RESULTS: Congenital hip dislocations were present in 100% of the patients. There was no attempt at reduction in 39% (25/64) of the hips. In the remaining 61% (39/64), the hips were treated with a variety of modalities fraught with complications. Of those treated, 85% (33/39) remain dislocated, the rest of the hips continue subluxated with acetabular dysplasia and pain. The group of hips that were not treated reported fewer complaints and limitation in daily activities compared with the hips that had attempts at reduction. CONCLUSIONS: Steel syndrome is a distinct clinical entity characterized by short stature, bilateral hip and radial head dislocation, carpal coalition, scoliosis, cavus feet, and characteristic facial features with dismal results for attempts at reduction of the hips. LEVEL OF EVIDENCE: Prognostic Study Level II.

The Vertical Expandable Prosthetic Titanium Rib in the treatment of spinal deformity due to progressive early onset scoliosis.

The Vertical Expandable Prosthetic Titanium Rib (VEPTR) is a technique developed for the treatment of progressive early onset scoliosis. This vertically placed device uses distraction to indirectly elongate the spine and chest, stabilizing the progression of the spinal deformity while preserving spinal growth. Thoracic spine and chest wall deformity are usually correlated; therefore, elongation of the chest wall will increase the space available for the lung and improve respiratory mechanics in patients with early onset scoliosis. We conducted a retrospective study of 17 patients with early onset scoliosis treated with the VEPTR technique. The medical records, imaging studies, and follow-up physical examinations were evaluated. The patient population consisted of 17 primary VEPTR implantations and 33 expansion surgeries with a mean follow-up of 25 months. Our results show that there was an improvement in the coronal plane deformity between the presurgical and postsurgical Cobb angles, preoperative Cobb angle of 59 degrees (range 38-77) to postoperative 35 degrees (range 10-70), resulting in an average decrease of 59% in the Cobb angle (P<0.001). The thoracic kyphosis was maintained at anatomically normal values. The surgical technique preserved the space available for the lung. The complication rate was 13%, which includes infection, device migration, and rib fracture. The analysis of the data shows that the natural history of the progressive spinal deformity was improved in all patients. This preliminary report reaffirms that the VEPTR implantation is a safe and efficient method for the treatment of early onset scoliosis.

Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome.

Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is an autosomal-recessive disorder characterized by abnormal vertebral segmentation and defects affecting spine formation, with complete bilateral fusion of the ribs at the costovertebral junction producing a "crab-like" configuration of the thorax. The shortened spine and trunk can severely affect respiratory function during early childhood. The condition is prevalent in the Puerto Rican population, although it is a panethnic disorder. By sequencing a set of candidate genes involved in mouse segmentation, we identified a recessive E103X nonsense mutation in the mesoderm posterior 2 homolog (MESP2) gene in a patient, of Puerto Rican origin and from the Boston area, who had been diagnosed with STD/JLS. We then analyzed 12 Puerto Rican families with STD probands for the MESP2 E103X mutation. Ten patients were homozygous for the E103X mutation, three patients were compound heterozygous for a second nonsense mutation, E230X, or a missense mutation, L125V, which affects a conserved leucine residue within the bHLH region. Thus, all affected probands harbored the E103X mutation. Our findings suggest a founder-effect mutation in the MESP2 gene as a major cause of the classical Puerto Rican form of STD/JLS.

Natural history of thoracic insufficiency syndrome: a spondylothoracic dysplasia perspective.

BACKGROUND: Spondylothoracic dysplasia is a condition in which bilateral chest wall deformity due to costovertebral rib fusion with shortening of the thoracic spine results in severe thoracic insufficiency syndrome and early death. Little is known about the long-term respiratory natural history of this disorder and the specific anatomic deformity. METHODS: We conducted a multicenter prospective and retrospective study of patients with spondylothoracic dysplasia. Medical evaluations, respiratory history, physical examination findings, radiographs, computed tomographic scans, and pulmonary function tests were studied. Anatomic, radiographic, and functional parameters for the disorder were established to determine the natural history of the thoracic insufficiency syndrome. RESULTS: Twenty-eight patients were identified. Eight patients had died in the neonatal period, and twenty were evaluated (eleven prospectively and nine retrospectively). The survivors were doing well clinically, but the average spirometric values were 27.9% of the predicted normal value for the forced vital capacity (FVC), 29.5% of the predicted normal value for the forced expiratory volume in the first second (FEV1), and 0.92 for the FEV1/FVC ratio, demonstrating a severe restrictive respiratory pattern. The computed tomographic scan lung volumes were an average of 28% of the expected values for age and gender. The thorax was stiff from rib fusion and was severely shortened posteriorly, averaging 24.2% of the predicted normal length. The thoracic spine was predominantly composed of block vertebrae, whereas in the lumbar region there were multiple hemivertebrae. Minimal scoliosis was seen, and there were no neurological deficits. CONCLUSIONS: Spondylothoracic dysplasia has a unique pathoanatomy of volume depletion deformity of the thorax with chest wall stiffness, resulting in thoracic insufficiency syndrome. Clinical tolerance of the restrictive lung disease in this disorder is impressive, but no clear reason has yet been identified for the clinical pulmonary health in the face of severe restrictive lung disease. Patients who survive infancy show no progression of congenital anomalies and can have a good quality of life. This disease may serve as a model of the natural history of thoracic insufficiency syndrome due to growth inhibition of the thoracic spine either as a result of congenital causes or secondary to surgical fusion early in life.

Orthopaedic manifestations of Bardet-Biedl syndrome.

Bardet-Biedl syndrome is an autosomal recessive disorder poorly characterized in the orthopaedic literature. Classic manifestations of the syndrome include pigmentary retinopathy, obesity, polydactyly, hypogonadism, and mild mental retardation. Previous reports have implied that orthopaedic findings are due to an epiphyseal dysgenesis inherent to the syndrome. The purpose of this study was to evaluate the orthopaedic manifestations of 27 patients with this syndrome. Detailed medical histories and physical examinations as well as pedigree analyses and radiographic bone surveys were performed. Orthopaedic findings included the following: 17 patients had postaxial polydactyly, 4 patients had scoliosis, 2 patients had tibia valga, 2 patients had tibia vara, and 1 patient had Legg-Calve-Perthes. The bone survey did not reveal any additional radiographic abnormalities. Based on these results, Bardet-Biedl syndrome patients do not have epiphyseal dysgenesis; their epiphyseal manifestations are probably the result of their obesity.

Controversies surrounding Jarcho-Levin syndrome.

PURPOSE OF THE REVIEW: Jarcho-Levin syndrome is an eponym that has been used to describe a variety of clinical phenotypes consisting of short-trunk dwarfism associated with rib and vertebral anomalies. This admixture of phenotypes under Jarcho-Levin syndrome has allowed some confusion in terms of phenotype, prognosis, and mortality. In the past 2 years, few papers have provided more insight into the clinical diagnosis, prognosis, and management of patient with these phenotypes. RECENT FINDINGS: Recently molecular, clinical, and radiologic data have allowed further characterization of these phenotypes. Based on these findings, we have divided these phenotypes into spondylothoracic dysplasia and spondylocostal dysostosis. SUMMARY: A better understanding of the distinct phenotypes under Jarcho-Levin syndrome will help clinicians to understand the pathological factors of the disease, establish mode of inheritance, provide adequate genetic counseling, prognosis, molecular diagnosis, and clinical management recommendations.