Although genetics has traditionally been associated with pregnancy, birth defects, and newborn screening, almost every disease is influenced in part by an individual's genetic makeup. Therefore, it is important to consider the impact of genetics in health and disease throughout an individual's lifetime.

Although genetics has traditionally been associated with pregnancy, birth defects , and newborn screening , almost every disease is influenced in part by an individual’s genetic makeup. Therefore, it is important to consider the impact of genetics in health and disease throughout an individual’s lifetime.

Rahman syndrome is a rare congenital anomaly syndrome recently described, which results from pathogenic variants in the HIST1H1E gene. The condition is characterized by variable somatic overgrowth, macrocephaly, distinctive facial features, intellectual disability, and behavioral problems. This report extends the genotype and clinical phenotype of HIST1H1E-associated Rahman syndrome.

Molecular testing has expanded exponentially in recent years with subsequent variants of uncertain significance (VUS) creating even more challenges for clinical practice. Clinicians oftentimes are restricted in their ability to perform functional testing as it is not routinely available clinically. Additionally, research groups may not be studying that particular gene at the time of results return. Epigenetic disorders may be particularly well-suited for further, non-invasive functional studies, which are now clinically available. Despite differing mechanisms and disease pathology impacting histone marks, epigenetic disorders show specific, global DNA methylation patterns that can separate from typical controls as well as from each disorder. We highlight three cases with clinical suspicion for an epigenetic disorder with subsequent ability to confirm diagnoses through a blood-based clinical test, the epigenetic signature. Case 1 was initially evaluated prenatally given findings of multiple congenital anomalies including intracranial, craniofacial and kidney malformations. Microarray was non-diagnostic followed by Neonatal Crisis Panel returning three VUSs in MUSK, CHD7 and NPHP4. The CHD7 variant was highly suspicious given the phenotype, but no further testing was available to be performed. Following delivery at 36 weeks, he was noted also to have a micropenis, sacral dimple, obstructive and central sleep apnea and feeding issues. Per previously published criteria, criteria, he had zero major signs and 2 minor signs of CHARGE syndrome. Despite this, his presentation was significantly suspicious for CHARGE syndrome, and episignature testing was ordered (EpiSign), which returned positive for CHARGE Syndrome. Temporal bone imaging revealed significant and typical abnormalities, and CHARGE syndrome management was enacted. Case 2 is a female who presented at 8 years of age with primary complaint of significant joint laxity. She also had mild hypotonia, chronic constipation, and ADHD and anxiety with an average IQ. A chromosomal microarray was normal, and whole exome sequencing revealed a de novo missense VUS in KMT2D. Further physical examination revealed her palpebral fissures were 3.0 cm (just under +2 SDs according to previously published criteria), persistence of the fetal finger pads, a high arched palate, but no dysmorphisms of nose or ears. Based on previously published international diagnostic criteria for Kabuki syndrome, she does not meet criteria for definite diagnosis. Episignature testing was ordered, which returned positive for Kabuki syndrome. Given the diagnosis, she was able to receive proper care directed for KS as well as support from the patient community from that time forward. Case 3 is a male who initially presented as a return to care with a past clinical diagnosis of Rubinstein Taybi Syndrome (RTS). At follow-up, he was 34 years old with complex medical history including history of developmental and intellectual disability, obstructive sleep apnea, multi-cystic kidney requiring nephrectomy, spondylolisthesis, history of vertebral compression fractures in teenage years, hypogonadotropic hypogonadism, short stature, history of failure to thrive and obesity, anxiety and suggestive physical features of RTS with broadening of thumbs and facial features. Targeted genetic testing revealed a VUS in CREBBP with subsequent epigenetic signature being consistent with RTS type 1. Molecular testing results including VUSs are a common occurrence. However, many times no further work-up is possible. Our cases underscore the importance for development and utilization of non-invasive diagnostic tools to ensure proper patient care and management can occur, thus maximizing patient outcomes. Furthermore, prenatal implementation of these technologies is needed as it would greatly improve prenatal counseling and planning given the increasing numbers of molecular testing being sent in the prenatal period.

Congenital factor V deficiency (FVD) is a rare bleeding disorder. In this study, we investigated the genetic basis in an African American patient with factor V activity 3%. Custom sequence capture and targeted next-generation (NGS) sequencing of the F5 gene were undertaken followed by PCR and Sanger sequencing. Two novel variants were identified. In silico analyses correlated clinically with the patient's factor V activity and hemorrhagic tendency. A review of the literature regarding these genomic alterations is presented. We described two novel mutations causing moderate FVD. The first, Chr1:g.169483698C>A with cDNA change (F5):c.6529-1G>T, occurred in a conserved nucleotide at the canonical acceptor splice site of intron 24. The second, Chr1:g.169515775C>T with cDNA change (F5):c.1667G>A, was a missense variant of exon 11, affecting a highly conserved amino acid in the A2 domain. Further research into the mechanisms of F5 mutations leading to FVD and residual factor V expression are needed.

Trisomy 12 is a rare autosomal aneuploidy. All postnatally diagnosed individuals with trisomy 12 have been mosaic for this chromosome abnormality. We herein report an infant girl presented at 2 weeks of age with severe congenital heart defect, tracheobronchomalacia, and dysmorphic features. All of the dysmorphic features of this patient fit into the known phenotype spectrum of mosaic trisomy 12, although this patient uniquely presented with macrocephaly. Tracheo-bronchomalacia has been described once previously but had a significant impact on this patient's clinical course. The patient passed away at 2-month-old due to cardiac and respiratory complications. Chromosomal single nucleotide polymorphism (SNP) microarray analysis on a peripheral blood sample from the patient revealed trisomy 12 in approximately 50% of cells. Concurrent fluorescence in situ hybridization analysis of uncultured blood cells detected a comparable level of trisomy 12 mosaicism. Compared to conventional cytogenetics, SNP microarray examines all nucleated cells without sampling bias, has an increased power to estimate mosaicism level, and can provide a quick assessment of the underlying mechanism. Here we demonstrate the utilization of SNP microarray in the clinical diagnosis of those once considered rare disorders but might have been missed by conventional cytogenetic techniques.