2022 Association of Professors of Human and Medical Genetics (APHMG) consensus-based update of the core competencies for undergraduate medical education in genetics and genomics.

PURPOSE: The field of genetics and genomics continues to expand at an unprecedented pace. As scientific knowledge is translated to clinical practice, genomic information is routinely being used in preventive, diagnostic, and therapeutic decision-making across a variety of clinical practice areas. As adoption of genomic medicine further evolves, health professionals will be required to stay abreast of new genetic discoveries and technologies and implementation of these advances within their scope of practice will be indicated. METHODS: The Association of Professors of Human and Medical Genetics previously developed medical school genetics core competencies, last updated in 2013. The competencies were reviewed and updated through a structured approach incorporating a modified Delphi method. RESULTS: The updated Association of Professors of Human and Medical Genetics core competencies are presented. Current revisions include competencies that are concise, specific, and assessable. In addition, they incorporate recent advances in clinical practice and promote equity and inclusion in clinical care. CONCLUSION: The 2022 competencies will serve as a guide for medical school leadership and educators involved in curriculum development, implementation, and assessment. Use of these competencies across the undergraduate medical curricula will foster knowledge, skills, and behaviors required in medical practice across a wide range of specialties.

Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies.

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.

The prevalence of congenital hearing loss in neonates with Down syndrome.

OBJECTIVE: To determine the prevalence of hearing loss in newborns with Down syndrome. STUDY DESIGN: We performed a cross-sectional, retrospective chart review of all infants with Down syndrome born at a university-affiliated hospital (n = 77) or transferred in to the associated pediatric hospital (n = 32) following birth at an outlying hospital between 1995 and 2010. We determined the rate of failure of newborn hearing screens, the proportion of infants lost to follow-up, and the rate of confirmed hearing loss, as well as the associations of risk factors for hearing loss with confirmed hearing loss. RESULTS: Of the 109 patients with hearing screening data, 28 failed their newborn hearing screen. Twenty-seven infants were referred for audiologic evaluation, and 19 completed the evaluation. Fifteen of these 19 infants (79%) had confirmed hearing loss. The prevalence of congenital hearing loss in this sample of neonates with Down syndrome was 15%. Exposure to mechanical ventilation was the sole known risk factor associated with hearing loss. In this study, the loss to follow-up rate for infants with positive hearing screens was 32%. CONCLUSION: Newborns with Down syndrome have a higher prevalence of congenital hearing loss compared with the total neonatal population (15% vs 0.25%). Continued monitoring of hearing is needed in children with Down syndrome.

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.