The internet (and now social media) has been a source of information about medical conditions and their treatments for some time (Bouwman et al., 2010; Dragusin et al., 2013; Finney Rutten et al., 2019; Jia et al., 2021; Wallace et al., 2022). Clinical geneticists may be confronted by patients or parents who have done internet “research” about potential diagnoses and treatments for their medical issues. While these suggested diagnoses might not be relevant at times, in some cases, these internet searches may reveal the correct diagnosis for rare diseases that would not have otherwise been considered by the provider (Bouwman et al., 2010; Greenwald, 2005). Through virtual one-hour interviews with patients or their caregivers (University of Kentucky IRB approved protocol #86093), we present the journey of seven families who came to their providers with the correct diagnosis ahead of their clinical genetics appointment (Table 1). For narrative clarity, we present their experiences in three sequential chronological stages that reflect their experiences. SGSH: c.734G>A (p.Arg245His)/c.892T>C (p.Ser298Pro) Parents of patients with undiagnosed genetic disorders may feel a strong motivation to discover their child's diagnosis. They often have seen and known their child in ways that were not possible for their medical providers. These parents may have access to diagnostically relevant information that is not available to their treatment team. The mother of Patient 6 said concerning her daughter “I'm seeing her movements and the way she behaves and her acts and just everything about her all day, every day, in every shape and every form of it, which is why I could see it, some of those little nuances that [her providers] could not see in that 30-minute session…. I can see why doctors can overlook certain things because you're not spending your life with these people to see the ins and outs of everything.” Parents of patients with undiagnosed genetic disorders and the patients themselves may feel unsure of where to turn or what to do. The dilemma of the patient and family can be compounded by the medical provider's lack of understanding of the situation. As the mother of Patient 3 said, “The most challenging part is physicians not being aware and being just as lost as you.” Prior to receiving the diagnosis of their child's genetic condition, many parents sensed something was wrong with their child but they had no explanation. Some felt guilty they might have done something wrong and worried they were to blame for their child's condition. The mother of Patient 6 said, “It was always this game for myself of, ‘What am I not doing right?’ Or, ‘What am I doing wrong?’ Maybe it's my fault.” The mother of Patient 4 wondered, “What did I do? What did I eat? Was it that ‘McFlurry’ that I had that one time when I was six months pregnant?” I did have somebody who was like, “Well, did you eat all organic when you were pregnant?” And it was just “Are you kidding me?” Little comments like that …. “Did anything happen while you were pregnant? Did you eat something weird? Did you get sick? Did you get a virus?” Those kinds of questions on their face sound well-meaning, but really they don't feel well-meaning when they're received.” I just burst into tears. I was crying so hard because he didn't have leukemia. And I was actually thinking that if he had leukemia, then I would have a path…. But not hitting another wall of nobody knows what's wrong with your child was, to me, worse than finding out your child didn't have cancer…. It tells you the mindset that you get into, the state of mind that you're in when you're just eight years of trying and trying. The mother of Patient 1 noted the awkwardness of being unable to tell others what was wrong with her child. She said, “And when you say you don't know, it's really hard because people don't believe you, for one, that he is really special needs, they question it.” ‘How do you not know?’ I can't even tell you how many times I've been asked, ‘How do you not know what he has?’ She also expressed a sense of isolation because “There is no organization for you for kids that don't have a diagnosis.” Two families were wrongly accused of abuse or neglect by their medical providers before the diagnosis was known. Patient 2 had chronic failure to thrive and severe nasal regurgitation (Figure 1a). Patient 2's pediatric gastroenterologist called the pediatrician and “said that it was a social issue” and that Patient 2's parents “were the problem.” Patient 2's feeding difficulties and failure to thrive resulted from his genetic disorder and were not his parents' fault. At 3 weeks of age, Patient 3 was discovered to have fractured ribs and arm contractures (Figure 1b,c). Her mother said “When they came back to us and told us about the fractures, they immediately followed up with, they contacted Child Protective Services. Without warning, without conversation, without explanation, it was ‘We found this. As a result, this is now taking place.’” The parents' interaction with Patient 3 in the hospital was monitored constantly. This unexpected situation was traumatic and fearful for the parents. Her mother said, “I've never cried so much in my life [as] during that hospital stay.” Patient 3's fractures and contractures were the result of her genetic disorder, not parental abuse. Many of the parents of patients in this study took the initiative to search their children's symptoms online and found answers for themselves. The mother of Patient 6 had concerns during infancy and went to her pediatrician by 1 year of age because her daughter was “never laughing” (Figure 1d,e). “I never got those baby giggles and I didn't understand why,” she said. Subtle concerns with her development persisted during childhood to the point that by third grade the mother “could tell she's regressing.” Through social media, she recognized that some of her daughter's traits were also present in a girl who appeared on her TikTok feed. “We had a pediatrician's appointment and I told her, I just said, ‘Listen, it sounds crazy. I saw a TikTok. This is what it is.’” After a referral to Genetics, her suspicion was confirmed. The mother of Patient 4 noticed her son's “face looks like us and his eyes are completely different” (Figure 1f). She also noticed he has long hair on his elbows, searched “hairy elbows” online, and “something called hairy elbow syndrome came up.” She found an older website with photos of the faces of children with the syndrome. She exclaimed: “And I almost fell out of my chair. And at that point, I had said a thousand times, oh, I know this is it! I know this is it!” Subsequent genetic testing proved she was correct. The mother of Patient 1 was approached by a person who visited her home and persistently urged her to look into the possibility that her son had a rare genetic condition. At first, the mother was skeptical, but later she looked this syndrome up online. She “scrolled through looking at all the kids, and I came across a boy that looked exactly like him (Figure 1g,h). And that's when I thought, “This actually might be it. This could be it.” She told her primary care physician she thought her son had this condition. Subsequent genetic testing proved she was correct. The mother of Patient 5 “went down the rabbit hole” and frequently searched online for information concerning symptoms such as “bulgy eyes, lump on head.” She “kept looking and looking” until she found a photograph of a little girl in Sweden who looked “exactly” like her daughter (Figure 1i). The mother said after receiving the diagnosis “the first thing I did was I looked over at my husband and I told him … ‘I knew it. I knew it.’” The geneticist confirmed the suspected diagnosis. Many participants in this study were glad they researched the symptoms and discovered the diagnosis for their cases. Some participants came away from their experience of facing symptoms, research, diagnosis, and treatment with new perspectives on their lives, values, and priorities. The mother of Patient 6 said the diagnosis of her daughter's genetic disorder “definitely took some of the burden off of my self-doubt of what maybe I was doing wrong or what I wasn't doing right, so that was helpful.” The mother of Patient 4 likewise noted, “The diagnosis was what helped the most.” She recalled that when her son was finally diagnosed she “was so excited” and her provider “laughed with me and she said, ‘I think you're the only person I've spoken with who was this excited that your son has a genetic disorder that causes all these problems.’ But I was ecstatic. I was so ecstatic that now I had a path. I had the name to call it. I had a goal. I have learned to just accept him for who he is and love him for who he is.” The mother of Patient 1 said, “I don't think people understand how much just being able to tell people what my kid has is instead of people questioning me, there's a lot of freedom in that.” Patient 7, an adult survivor with Fabry disease (Figure 1j), felt his own research in his case made “a huge difference” and he probably would not be alive today without it. His struggle with Fabry disease helps him to “appreciate life every day.” He realizes “none of us are guaranteed another year or two years or even tomorrow, so make the most you can with the current day and give thanks for that.” The mother of Patient 2 said her relationship with her husband has changed for the better. Their son's health crisis caused them to “lean more towards each other” and say to each other that “you and I need to take care of ourselves and our relationship.” What we providers see as a “diagnostic odyssey” is for patient's families an emotional odyssey (Figure 2). In some cases, these caregivers were encouraged and helped by their providers who served as advocates for them. In other cases, they were dismissed, not listened to, merely tolerated, or even suspected of wrongdoing by some providers. Some caregivers felt judged by others. A health crisis that started with negative feelings of guilt, shame, blame, and isolation became the driving factor to take matters into their own hands to find the answer they were seeking. In addition to the expected relief of finding what eluded them for so long, these families were able to find comfort in the connections they were able to establish. They became their child's best advocate. Some expressed hope that in the future more providers will be familiar with genetic disorders and their symptoms. These seven cases demonstrate how patients with genetic disorders and their caregivers became active and significant participants in their care. They were strongly motivated to find answers in these cases, they had access to needed information, and they were on the right track. Genetics providers should be open to discussing the relevance of information and insights offered by patients and their caregivers, and collaborate with them to provide the best care. Robert B. Slocum: Conceptualization, formal analysis, writing—original draft, and writing—review and editing. Anna C. E. Hurst: Data analysis, writing—review and editing. Ellis Shelley: Conceptualization, data analysis, writing—review and editing. Lisa Berry: Data analysis, writing—review and editing. Robert Hopkin: Data analysis, writing—review and editing. Alyssa Rippert: Data analysis, writing—review and editing. Elizabeth Bhoj: Data analysis, writing—review and editing. John M. Graham Jr: Data analysis, writing—review and editing. Katheryn Grand: Data analysis, writing—review and editing. Aixa Gonzalez: Data analysis, writing—review and editing. Yuri A. Zarate: Conceptualization, formal analysis, writing—original draft, and writing—review and editing. The authors would like to thank all participating families. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Background: Hereditary spastic paraplegia (HSP) encompasses several rare genetic disorders characterized by progressive lower extremity spasticity and weakness caused by corticospinal tract degeneration. Published literature on genetically confirmed pediatric HSP cases is limited.Methods: We conducted a retrospective review of childhood-onset HSP cases followed in the neuromuscular clinics at Children's and Emory Healthcare in Atlanta. Clinical presentation, family history, examination, electrodiagnostic data, neuroimaging, genetic test results, comorbidities, and treatment were recorded.Results: Sixteen patients with HSP (eight males, eight females) with a mean age 19 years +/- 15.7 years were included. Ten patients (66%) presented with gait difficulty. Seven (44%) were ambulatory at the last clinic follow-up visit with an average disease duration of 7.4 years. Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1), SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MTATP6 (1), and ATL1 (1). Symptom onset to genetic confirmation on an average was 8.2 years. Sensory motor axonal polyneuropathy was found in seven patients, and two exhibited cerebellar atrophy on magnetic resonance imaging (MRI) of the brain. Neurological comorbidities included developmental delay (n = 9), autism (n = 5), epilepsy (n = 3), and attention-deficit/hyperactivity disorder (n = 2).Conclusions: In our study, a significant proportion (70%) of subjects with childhood-onset HSP had comorbid neurocognitive deficits, polyneuropathy with or without neuroimaging abnormalities, and rare genetic etiology. Genetic diagnosis was established either through inherited genetic neuropathy panel or whole-exome sequencing, which supports the utility of whole-exome sequencing in aiding in HSP diagnosis.(c) 2022 Published by Elsevier Inc.

Elevated total plasma homocysteine (hyperhomocysteinemia) is a marker of cardiovascular, thrombotic, and neuropsychological disease. It has multiple causes, including the common nutritional vitamin B12 or folate deficiency. However, some rare but treatable, inborn errors of metabolism (IEM) characterized by hyperhomocysteinemia can be missed due to variable presentations and the lack of awareness. The aim of this study is to identify undiagnosed IEM in adults with significantly elevated homocysteine using key existing clinical data points, then IEM specific treatment can be offered to improve outcome. We conducted a retrospective study with data mining and chart review of patients with plasma total homocysteine >30 μmol/L over a two-year period. We offer biochemical and genetic testing to patients with significant hyperhomocysteinemia without a clear explanation to diagnose IEM. We identified 22 subjects with significant hyperhomocysteinemia but no clear explanation. Subsequently, we offered genetic testing to seven patients and diagnosed one patient with classic homocystinuria due to cystathionine beta-synthase deficiency. With treatment, she lowered her plasma homocysteine and improved her health. This study stresses the importance of a thorough investigation of hyperhomocysteinemia in adults to identify rare but treatable IEM. We propose a metabolic evaluation algorithm for elevated homocysteine levels.

To the Editor The MED12 gene has an important role in neuronal gene silencing (Ding et al., 2008; Graham Jr & Schwartz, 2013) and has been associated with four distinct X-linked intellectual disability (ID) conditions: FG syndrome, Lujan syndrome, Ohdo syndrome, and nonspecific ID. Its gene product is part of the large Mediator complex comprised of 31 subunits arranged in four modules that interacts with RNA polymerase II and plays a critical role in regulating transcription (Yin & Wang, 2014). The complex is involved in cell growth, development, and differentiation through epigenetic regulation, transcriptional elongation, termination, mRNA processing, noncoding RNA activation, and super enhancer formation (Graham Jr & Schwartz, 2013). The four MED12-related conditions share ID as a common phenotype with differing dysmorphic features and/or comorbidities. It has become apparent that females can also have ID as a result of variants in MED12 (Charzewska et al., 2018; Lesca et al., 2013; Polla et al., 2020; Rubinato et al., 2020). The phenotypic spectrum seen varies from no cognitive impairment to profound ID, with dysmorphic features such as prominent forehead, bitemporal narrowing, hypertelorism, and down-slanting palpebral fissures (Charzewska et al., 2018; Polla et al., 2020; Rubinato et al., 2020). When affected, females may not fit into a specific phenotype, and de novo variants appear to increase the risk of severe ID (Polla et al., 2020). Skewed Xinactivation explains some but not all cases (Charzewska et al., 2018; Lesca et al., 2013; Polla et al., 2020; Prontera et al., 2016). Here, we present two females with pathogenic variants in MED12 and vastly differing phenotypes (Table 1). A nonhuman subjects research determination was obtained from the Emory University Institutional Review Board. Informed consent was obtained prior to submission. The authors have no conflicts of interest respecting this manuscript. P1 is a female who presented to Genetics at 18-years-old due to mild intellectual impairment and dysmorphic features. She was born at 40 weeks gestation with a birth weight of 3515 g. Developmental milestones were mildly delayed, sitting at 9 months old and walking at 16 months old. She received speech therapy for articulation issues. Later, she was diagnosed with attention deficit disorder and executive functioning defects, completing high school with great difficulty. She did not learn how to drive. She has depression and anxiety treated with psychotherapy. Her medical problems include mild right-sided hearing loss, strabismus corrected with patching, myopia and astigmatism, positional orthostatic tachycardia syndrome with normal echocardiogram, and mild bilateral hip dysplasia. She has hiatal hernia, gastroesophageal reflux, constipation, and irritable bowel syndrome. Dysmorphic features include round eyes, prominent nose, short philtrum, small hands and feet, and bilateral fifth finger clinodactyly. Extensive negative workup included chromosomal microarray, FMR1 repeat, N-glycan, O-glycan, 7-dehydrocholesterol, plasma amino acids, and urine organic acid analysis. Brain MRI was normal. An ID panel revealed a variant of uncertain significance in the MED12 gene c.4669T>C (p.W1557R, NM_005120.3), confirmed to be de novo with subsequent parental testing, resulting in the variant being reclassified to likely pathogenic by the laboratory. The variant fulfills the following criteria according to the ACMG classification (Richards et al., 2015): PS2 for being de novo, PM2 for being absent in the gnomAD exomes and genomes databases, and PP3 for being predicted to be deleterious by multiple lines of computational evidence (DANN score [Quang et al., 2015] of 0.9964, SIFT: damaging, PROVEAN: damaging). We do not count PP5 as the ClinVar entry for this variant corresponds to this case. X chromosome inactivation analysis was inconclusive due to homozygosity for the polymorphism in the AR gene used in the assay. We concluded that P1's phenotype (Figure 1) best fits Lujan syndrome. P2 is a female who first presented to genetics clinic at age 7 years in the year 2004, with moderate ID, obesity, hypotonia, developmental delays, and behavioral problems. The pregnancy history was remarkable for severe IUGR, born at 40 weeks with birth weight 1800 g (Z score 5.39), and an abnormal placenta. Patient had a brain Received: 5 February 2021 Revised: 8 March 2021 Accepted: 7 April 2021

The primary mode of imaging in hypertrophic cardiomyopathy (HCM) is transthoracic echocardiography (TTE). However, in adults inadequate acoustic windows lead to poor quantification of myocardial thickness compared with cardiac magnetic resonance (CMR) imaging. In comparison, children have better acoustic windows and TTE measurements of wall thickness might be more accurate. The aim of this study was to assess the performance of TTE compared with CMR for the assessment of myocardial thickness in children with HCM.Nineteen children (median age, 12.7 years; range, 8.4-18.4 years) with known HCM were studied using TTE and CMR imaging on the same day. The left ventricle was measured off-line using the standard 16-segment model.With CMR imaging 304 (19 × 16) segments were analyzable whereas only 263 were analyzable using echocardiography. Wall thickness measurements according to TTE were greater than those according to CMR imaging in the basal anterolateral, midventricular anterior and anterolateral and apical inferior, lateral and septal segments and smaller for the midventricular inferior and inferoseptal segments. Reproducibility of CMR and TTE measurements was assessed using the intraclass correlation coefficient (ICC). CMR measurements showed excellent intrareader (ICC, 0.929-0.991) and moderate inter-reader (ICC range, 0.512-0.991) reproducibility. TTE measurements revealed moderate intrareader (ICC, 0.575-0.942) and poor inter-reader (ICC range, −1.02 to 0.939) reproducibility.Echocardiography incompletely assesses circumferential myocardial thickness in a proportion of pediatric patients with HCM. Echocardiography under- and overestimates maximum wall thickness compared with CMR, depending on the location. Measurements using CMR are more reproducible than those obtained using echocardiography.Le mode d’imagerie principal de la cardiomyopathie hypertrophique (CMH) est l’échocardiographie transthoracique (ETT). Toutefois, les fenêtres acoustiques inadéquates chez les adultes entraînent une mauvaise quantification de l’épaississement du myocarde comparativement à l’imagerie par résonance magnétique (IRM) cardiaque. Par comparaison, comme les enfants ont de meilleures fenêtres acoustiques, les mesures de l’ETT de l’épaississement de la paroi seraient plus précises. L’objectif de la présente étude était d’évaluer la performance de l’ETT par rapport à celle de l’IRM cardiaque dans l’évaluation de l’épaississement du myocarde chez les enfants atteints de CMH.Dix-neuf enfants (âge médian, 12,7 ans; étendue, 8,4-18,4 ans) atteints d’une CMH connue ont fait l’objet d’une étude au moyen de l’ETT et de l’IRM cardiaque le même jour. Le ventricule gauche a été mesuré hors ligne à l’aide du modèle habituel à 16 segments.Au moyen de l’IRM cardiaque, 304 (19 × 16) segments ont été analysés tandis que seulement 263 segments étaient analysables au moyen de l’échocardiographie. Les mesures de l’épaississement de la paroi selon l’ETT étaient plus grandes que celles selon l’IRM cardiaque dans les segments basaux antérolatéraux, médioventriculaires antérieurs et antérolatéraux et apicaux inférieurs, latéraux et septaux, et plus petites dans les segments médioventriculaires inférieurs et inféroseptaux. La reproductibilité des mesures de l’IRM cardiaque et de l’ETT a été évaluée à l’aide du coefficient de corrélation intraclasse (CCI). Les mesures de l’IRM cardiaque ont montré une excellente reproductibilité intraobservateur (CCI, 0,929-0,991) et une reproductibilité interobservateur modérée (étendue du CCI, 0,512-0,991). Les mesures de l’ETT ont révélé une reproductibilité intraobservateur modérée (CCI, 0,575-0,942) et une reproductibilité interobservateur médiocre (étendue du CCI, −1,02 à 0,939).L’échocardiographie évalue de façon incomplète l’épaississement myocardique circonférentiel chez un certain nombre de patients de pédiatrie atteints de CMH. L’échocardiographie sous-estime et surestime l’épaississement maximal de la paroi comparativement à l’IRM cardiaque, selon la localisation. Les mesures au moyen de l’IRM cardiaque sont plus reproductibles que celles obtenues au moyen de l’échocardiographie.

Mosaicism in Cornelia de Lange syndrome (CdLS) has been reported in clinically diagnosed CdLS patients with negative molecular testing using blood as the specimen, particularly in the NIPBL gene. Here we report a novel mosaic variant in SMC1A identified in the buccal swab DNA of a patient with a mild CdLS phenotype. Our patient presented with global developmental delay, dysmorphic features, microcephaly, and short stature, with no limb defect. Face2Gene, a digital tool that analyzes facial morphology, demonstrated a 97% match between our patient and the CdLS gestalt. An initial next-generation sequencing (NGS)-based CdLS panel test, including NIPBL , HDAC8 , RAD21 , SMC1A , and SMC3 , completed using DNA isolated from leukocytes, was negative, and subsequent trio exome sequencing was nondiagnostic. The exome identified biallelic variants of uncertain significance in a candidate gene, NSMCE2 . In the pursuit of a molecular diagnosis, a second NGS-based CdLS panel test was ordered on a buccal swab specimen and a novel variant, c.793_795delGAG (p.Glu265del) in SMC1A , was detected at 60% mosaicism. Retrospective analysis of the former panel and exome data revealed the SMC1A variant at 4% and 2%, respectively, both far below standard reporting thresholds. Given that mosaicism has been frequently reported in CdLS, we suggest selecting a different tissue for testing in clinically suspected CdLS cases, even after negative molecular results via blood specimen.

The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.

The authors declare no conflicts of interest related to this report.