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Background: The Michigan State College of Human Medicine began as an experiment to teach medical students in community-based settings and to create a primary care workforce for the state. Decades later, CHM faced internal and external challenges that spurred creation of a new curriculum - the Share Discovery Curriculum - founded on learning by doing and other learning theories., Methods: A curricular design group (CDG) developed guiding principles for reform. Based on this, pedagogies and structures were selected to achieve this vision and developed into a curricular structure. Components of the first-year curriculum were piloted with a group of students and faculty members., Results: Six guiding principles were endorsed, grounded in learning theories such as Dewey's Learning by Doing. Based upon these, several key features of the new curriculum emerged: learning communities; one-on-one coaches for students; symptom-based presentations for content; simulation, authentic clinical tasks, flipped classrooms, and modified practice-based learning as primary teaching modalities; early, integrated clinical and scientific learning; milestones as course learning objectives; and a multidimensional, competency-based assessment system., Discussion: The process and outcomes described here are intended as an exemplar for schools undertaking curricular change. Early stakeholder engagement, faculty development, sustainable administrative systems, and managing complexity are core to the success of such endeavors.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population., (© 2023 Wiley Periodicals LLC.)

Background: Prostate-specific antigen (PSA) screening may reduce death due to prostate cancer but leads to the overdiagnosis of many cases of indolent cancer. Targeted use of PSA screening may reduce overdiagnosis. Multimarker genomic testing shows promise for risk assessment and could be used to target PSA screening., Methods: To test whether counseling based on the family history (FH) and counseling based on a genetic risk score (GRS) plus FH would differentially affect subsequent PSA screening at 3 months (primary outcome), a randomized trial of FH versus GRS plus FH was conducted with 700 whites aged 40 to 49 years without prior PSA screening. Secondary outcomes included anxiety, recall, physician discussion at 3 months, and PSA screening at 3 years. Pictographs versus numeric presentations of genetic risk were also evaluated., Results: At 3 months, no significant differences were observed in the rates of PSA screening between the FH arm (2.1%) and the GRS-FH arm (4.5% with GRS-FH vs. 2.1% with FH: χ 2 = 3.13, P = .077); however, PSA screening rates at 3 months significantly increased with given risk in the GRS-FH arm (P = .013). Similar results were observed for discussions with physicians at 3 months and PSA screening at 3 years. Average anxiety levels decreased after the individual cancer risk was provided (P = .0007), with no differences between groups. Visual presentation by pictographs did not significantly alter comprehension or anxiety., Conclusions: This is likely the first randomized trial of multimarker genomic testing to report genomic targeting of cancer screening. This study found little evidence of concern about excess anxiety or overuse/underuse of PSA screening when multimarker genetic risks were provided to patients. Cancer 2016;122:3564-3575. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

The first practice based competencies (PBCs) for the field of genetic counseling were adopted by the American Board of Genetic Counseling (ABGC), 1996. Since that time, there has been significant growth in established and new work settings (clinical and non-clinical) and changes in service delivery models and the roles of genetic counselors. These changes prompted the ABGC to appoint a PBC Task Force in 2011 to review the PBCs with respect to their current relevance and to revise and update them as necessary. There are four domains in the revised PBCs: (I) Genetics Expertise and Analysis (II) Interpersonal, Psychosocial and Counseling Skills (III) Education and (IV) Professional Development and Practice. There are 22 competencies, each clarified with learning objectives or samples of activities and skills; a glossary is included. New competencies were added that address genomics, genetic testing and genetic counselors' roles in risk assessment, education, supervision, conducting research and presenting research options to patients. With PBCs serving as the pre-defined abilities or outcomes of training, graduating genetic counselors will be well prepared to enter the field with a minimum level of skills and abilities. A description of the Task Force's work, key changes and the 2013 PBCs are presented herein.

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution., (© 2015 by The American Society of Hematology.)

The microcephaly-lymphedema-chorioretinal dysplasia (MLCRD) syndrome is a distinct microcephaly syndrome. The hallmark features, microcephaly, chorioretinopathy, and lymphedema are frequently recognized at birth. Another clinical entity, the chorioretinal dysplasia, microcephaly and mental retardation syndrome (CDMMR) is a highly overlapping syndrome characterized by more variable lymphedema. Recently, heterozygous mutations in KIF11, a gene encoding a critical spindle motor protein of the Kinesin family, have been reported in individuals with MLCRD, and in individuals with CDMMR. This finding is suggestive of a single clinically variable spectrum. Here, we report on de novo novel mutations of KIF11 in five individuals with severe microcephaly, marked simplification of the gyral pattern on neuroimaging, bilateral chorioretinopathy, and developmental delay. Three patients had congenital lymphedema, and one had congenital bilateral sensorineural hearing loss. This report, therefore, further expands the clinical and molecular spectrum of KIF11-associated microcephaly., (© 2014 Wiley Periodicals, Inc.)

A 16 year-old girl with pentasomy X mosaicism (47,XXX(1) 48,XXXX(12)/49,XXXXX) presented with primary amenorrhea. She had epicanthal folds, long philtrum, high-arched palate, facial asymmetry, short webbed neck, low posterior hairline, mild scoliosis, cubitus valgus, mental retardation and clinodactily. She was diagnosed with osteoporosis and premature ovarian failure.

An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the hands and feet and define and illustrate the terms that describe the major characteristics of the hands and feet.

The oral-facial-digital syndromes (OFDS) result from the pleiotropic effect of a morphogenetic impairment affecting almost invariably the mouth, face and digits. Other organ systems can be involved, defining specific types of OFDS. To date, 13 types have been distinguished based on characteristic clinical manifestations. An updated list of these types is provided and recent molecular data are discussed., ((c) 2007 Wiley-Liss, Inc.)

The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.

Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited, genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals. Most mutations affect either the triple-helical domain of the protein or the expression of one COL5A1 allele. We identified a novel splice-acceptor mutation (IVS4-2A-->G) in the N-propeptide-encoding region of COL5A1, in one patient with EDS type I. The outcome of this mutation was complex: In the major product, both exons 5 and 6 were skipped; other products included a small amount in which only exon 5 was skipped and an even smaller amount in which cryptic acceptor sites within exon 5 were used. All products were in frame. Pro-alpha1(V) chains with abnormal N-propeptides were secreted and were incorporated into extracellular matrix, and the mutation resulted in dramatic alterations in collagen fibril structure. The two-exon skip occurred in transcripts in which intron 5 was removed rapidly relative to introns 4 and 6, leaving a large (270 nt) composite exon that can be skipped in its entirety. The transcripts in which only exon 5 was skipped were derived from those in which intron 6 was removed prior to intron 5. The use of cryptic acceptor sites in exon 5 occurred in transcripts in which intron 4 was removed subsequent to introns 5 and 6. These findings suggest that the order of intron removal plays an important role in the outcome of splice-site mutations and provide a model that explains why multiple products derive from a mutation at a single splice site.

We present a patient with all the physical characteristics of Lujan-Fryns syndrome, including Marfanoid habitus, mild general hypotonia, hypernasal voice, normal testicular size, and distinct craniofacial anomalies. Despite the presence of impaired mental abilities in many areas, this young man showed intact concrete problem-solving skills under structured, interactive conditions. In addition, he did not demonstrate any of the psychiatric features that have often been reported with this syndrome. We conclude that Lujan-Fryns syndrome can be associated with partial preservation of neurobehavioral abilities., (Copyright 2001 Wiley-Liss, Inc.)

We report on a patient with ocular-ectodermal syndrome who was previously described in 1993 [Am J Med Genet (1993) 45:764-766]. This boy has now developed additional manifestations, including giant cell granulomas and non-ossifying fibromas. This adds to the list of phenotypic manifestations of this condition.

We report on a child we believe may have the same condition described in five children by Burn et al., in 1992 (Clin Dysmorphol 1:137-144). Component manifestations include choanal atresia, cardiac defects, prominent ears, hearing loss, and minor facial anomalies. Our patient also has rather significant short stature, thus adding to the variable phenotype of this condition.

We report on a patient born to consanguineous parents and presenting with pseudopapilledema, mixed hearing loss, and minor facial and limb anomalies. To our knowledge, there is just one similar description of this syndrome in three members of a Brazilian kindred whose parents were also consanguineous, suggesting autosomal recessive inheritance. We compare the findings of our patient with these previous reported cases and discuss the differential diagnoses of this new syndrome, which we suggest be named the acro-oto-ocular syndrome.

Three unrelated infants presented with radiographic punctate calcifications, nasal hypoplasia, and abnormalities of the spine. Additional anomalies included cupped ears in 2 patients and one each with Dandy-Walker malformation with hydrocephaly, congenital cataracts, and peripheral pulmonary artery stenosis. The mothers of these 3 patients had chronic conditions associated with intestinal malabsorption requiring total parenteral nutrition for varying periods of time. The underlying causes of malabsorption were celiac disease, short bowel syndrome secondary to surgical resection, and jejuno-ileal bypass, respectively. Bleeding diathesis occurred in one mother requiring vitamin K supplementation during the second and third trimesters of pregnancy. We speculate that the chondrodysplasia punctata and other abnormalities in these children were caused by an acquired maternal vitamin K deficiency manifested during early pregnancy. However, the involvement of other vitamin deficiencies cannot be excluded. Thus, vitamin K deficiency of the embryo secondary to maternal malabsorption appears to be a third vitamin K-related mechanism leading to chondrodysplasia punctata in addition to warfarin embryopathy and epoxide reductase deficiency (pseudo-warfarin embryopathy).

We describe 13 unrelated children with abnormalities of somatic growth, face, brain, and connective tissue including vasculature. Although the condition in these children falls under the general group of disorders known as cutis marmorata telangiectatica congenita (CMTC), the constellation of abnormalities appears to constitute a distinct and easily recognizable phenotype within this general group. In contrast to most children reported with CMTC, children in this subgroup have a high risk for neurologic abnormalities, including developmental delay, mental retardation, megalencephaly, and hydrocephalus. Early recognition of this condition is important for appropriate surveillance for known complications and parental counseling.

The oral-facial-digital syndromes (OFDS) have in common minor facial and oral anomalies (including tongue lobulation and/ or hamartomas, accessory frenula, and alveolar anomalies) and variable digital defects such as polydactyly. The classification based on the presence of additional findings [Toriello, 1988, 1993] is not perfect, as many reported examples of a particular OFDS have some other condition. Here we describe six children, all diagnosed as having OFDS IV (OFDS with tibial defects), whose manifestations illustrate the apparent genetic heterogeneity.

Oculodentodigital syndrome (ODD) is a congenital, autosomal dominant disorder which affects the development of the face, eyes, limbs and dentition. Spastic paraparesis is thought to be an occasional manifestation of the disorder. Type III syndactyly, which occurs as part of ODD, has also been reported to occur as an isolated entity. In the current investigation, a total genome search for the location of the ODD locus was instigated and linkage to polymorphic markers located on chromosome 6q established (pairwise Zmax = 9.37; theta = 0.001). Analysis of a large family with type III syndactyly, but atypical facial features, further suggested that isolated type III syndactyly is also located in this same region of the genome.

Congenital pulmonary lymphangiectasis is a rare anomaly that is causally heterogeneous. It can occur as either an isolated finding or one manifestation of several multiple congenital anomaly syndromes. We describe a child with congenital pulmonary lymphangiectasis and the anomalies who likely has a provisionally unique condition.

Chondrodysplasia punctata, a skeletal dysplasia with craniofacial dysmorphism and joint contractures can occur with rhizomelia, mesomelia or both. The rhizomelic form is generally lethal, whereas one form of mesomelic chondrodysplasia punctata has been described that is associated with a presumably normal lifespan and intelligence. We describe a case of a fetus suspected prenatally of having rhizomelic chondrodysplasia punctata, who was subsequently diagnosed at 1.5 years of age to have the tibia-metacarpal form of chondrodysplasia punctata. The prenatal sonographic findings of second-trimester micromelic bone shortening and third-trimester proximal femoral stippling may be present in the rhizomelic form but are not specific to this condition.