Niri F, Radziwon A, Mah R
… +4 more, Sankila EM, Wang NK, Hume S, MacDonald IM
Am J Med Genet A
· 2026 Jun · PMID 41714298
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To investigate the molecular cause of choroideremia in two unrelated patients with no detectable mutations in the CHM gene. Two unrelated patients were examined by an ophthalmologist to obtain a clinical diagnosis. Patie...To investigate the molecular cause of choroideremia in two unrelated patients with no detectable mutations in the CHM gene. Two unrelated patients were examined by an ophthalmologist to obtain a clinical diagnosis. Patient and control cells were cultured and used as a source of DNA, RNA, and protein for analysis. Exonic regions of CHM were Sanger sequenced and copy number analysis was performed by multiplex ligation-dependent probe amplification. mRNA transcripts were analyzed by Sanger sequencing from synthesized cDNA. Protein expression was probed with western blot analysis. Suspecting an inversion, PCR in one case and inverse PCR in the second case were employed to locate the precise DNA breakpoints. Patient 1 and 2 were clinically diagnosed with choroideremia by experienced ophthalmologists. In both cases, sequencing of the promoter and coding regions of the CHM gene revealed no mutation and copy number analysis of the gene did not detect the presence of any large deletions or duplications. RNA obtained from the patient cells showed only a partial transcript in patient 1, and an abnormal CHM splice isoform in patient 2. The results from RNA and DNA analyses suggested that both patients' genomic DNA might contain an inversion mutation. In patient 1, a long-range PCR product amplified over two breakpoints confirmed an inversion event. This 6 kb inversion spanned from the 5'UTR to the first intron (NM_000390.4(CHM): c.[-836_-826del; 49 + 5526_49 + 5856del; -825_49 + 5525inv; insCGTCT].). In patient 2, inverse PCR revealed a different novel inversion of approximately 85 kb, spanning from intron 2 to intron 8 (NM_000390.4(CHM):c.116 + 6659_1166 + 20670inv). To detect these two inversions in future choroideremia samples, multiplex PCR assays were developed that produce distinct banding patterns that are diagnostic for these two mutations. We have identified inversion mutations in the CHM gene resulting in choroideremia. Though uncommon, inversions should be investigated as a possible cause of the disease in CHM patients, especially for those in whom no point mutations or copy number variants are found.
Crocker K, O'Toole J, Pearse L
… +9 more, Margrill J, Khan A, Chopra M, Innes AM, Kainz H, Margrill H, Salazar K, Schwarze L, Krantz ID
Am J Med Genet A
· 2026 Jun · PMID 41714173
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The inaugural ReNU Hope Conference and Scientific Symposium was held from July 23-25, 2025 in Long Island, New York. This historic conference brought together the researchers responsible for the groundbreaking discovery...The inaugural ReNU Hope Conference and Scientific Symposium was held from July 23-25, 2025 in Long Island, New York. This historic conference brought together the researchers responsible for the groundbreaking discovery of RNU4-2/ReNU syndrome, families, scientists, clinicians, trainees, therapeutic developers, and industry leaders from around the world. The key themes that emerged included: (1) Early recognition and diagnosis of ReNU Syndrome, (2) optimizing clinical care for this complex condition, (3) the importance of the family experience, (4) a need to elucidate the underlying genetic mechanism, (5) a need for quality natural history data and validated endpoints, and (6) exploring approaches to therapeutic development. This summary provides a broad overview of the conference, highlights the key presentations and discussions, and delineates priorities moving forward.
Kessler CM, Schuler BA, Jasper EA
… +3 more, Talbert J, Duncan L, Mosera M
Am J Med Genet A
· 2026 Jun · PMID 41704091
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The objective of this study is to describe outcomes of rapid exome (rES) and rapid genome sequencing (rGS) in an inpatient setting. This is a retrospective cohort of inpatients with rES or rGS during their hospitalizatio...The objective of this study is to describe outcomes of rapid exome (rES) and rapid genome sequencing (rGS) in an inpatient setting. This is a retrospective cohort of inpatients with rES or rGS during their hospitalization between April 2016 and November 2023. Medical records were reviewed to measure primary outcomes: diagnostic yield, medical management changes, and anticipatory guidance updates. Descriptive analysis and formal comparisons (Welch's t-test with post hoc power analysis, Fischer's exact test) were performed, with rES and rGS comparisons limited to 2023 due to test distribution. Of 95 patients, most (74.7% [71/95]) were < 12 months old and admitted in neonatal (44.2% [42/95]) or pediatric (29.5% [28/95]) intensive care units. Common indications for rapid sequencing included multiple congenital anomalies (24.2% [23/95]), neurological concerns (23.3% [22/95]), and acute illness (16.8% [16/95]). Mean turnaround time of testing significantly shortened for rES from 2021 (13.2 [SD = 5.9] days) to 2023 (8.1 [SD = 4.1] days) (p-value = 0.018; power = 0.74). Diagnostic yield was 29.5% (28/95) and did not significantly differ between rES (13.6% [3/22]) and rGS (35.0% [7/20]) (p-value = 0.15). Sequencing led to medical management changes (86.0% [74/86]) and anticipatory guidance updates (41.4% [39/95]) with similar rates observed in diagnostic and non-diagnostic tests. Our findings suggest rES or rGS implementation may influence diagnosis and care strategies in critically ill patients.
Çetinkaya D, Çavdarlı B, Kırat E
… +1 more, Kılıç E
Am J Med Genet A
· 2026 Jun · PMID 41703727
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3MC syndrome is a rare congenital malformation disorder caused by biallelic pathogenic variants in COLEC10, COLEC11, and MASP1. It is characterized by distinctive craniofacial anomalies, growth retardation, developmental...3MC syndrome is a rare congenital malformation disorder caused by biallelic pathogenic variants in COLEC10, COLEC11, and MASP1. It is characterized by distinctive craniofacial anomalies, growth retardation, developmental delay, and variable systemic findings. Here, we report seven previously unreported patients with 3MC syndrome from five unrelated families. The cohort included five females and two males, aged 1-10 years. All patients exhibited characteristic craniofacial features, including hypertelorism, blepharoptosis, highly arched eyebrows, and epicanthus inversus. Cleft lip and/or palate were present in six patients, caudal appendage in four, congenital heart disease in two, hearing loss in four, and periumbilical anomalies in six. All patients showed neuromotor developmental delay. Molecular analysis identified novel pathogenic variants in COLEC10 in five patients and pathogenic alterations in MASP1 in two patients, including an exon-level deletion. These findings expand the clinical and molecular spectrum of 3MC syndrome and highlight the value of comprehensive molecular testing in its diagnosis.
Cipri S, Cacchione A, Agolini E
… +13 more, Verrigni D, Novelli A, Pepi C, De Palma L, De Benedictis A, Carai A, Barresi S, Rossi S, Alaggio R, Colafati GS, D'Orazio C, Boccuto L, Mastronuzzi A
Am J Med Genet A
· 2026 Jun · PMID 41700448
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Loss-of-function variants in the WW Domain Containing Adaptor with Coiled-Coil (WAC) gene are associated with DeSanto-Shinawi syndrome (DESSH), a rare autosomal dominant neurodevelopmental disorder usually with onset cha...Loss-of-function variants in the WW Domain Containing Adaptor with Coiled-Coil (WAC) gene are associated with DeSanto-Shinawi syndrome (DESSH), a rare autosomal dominant neurodevelopmental disorder usually with onset characterized by global developmental delay appearing in infancy or early youth, intellectual disability, seizures, autism spectrum disorder, attention-deficit/hyperactivity disorder, hypotonia, dysmorphic features at the level of the skull and face. The protein encoded by the WAC gene links and regulates gene transcription and monoubiquitination of histone H2B to "Lys-120" (H2BK120ub1). It also acts in the regulation of cell cycle checkpoint activation in response to DNA damage, and the RING finger 20/40 (RNF20/40)/WAC complex has been proven to act as an interactor with p53. We describe a 15-year-old boy with a diagnosis of DESSH associated with a WAC variant and a polymorphous low-grade neuroepithelial tumor of the young associated with an FGFR2(ex17):INA(ex2) fusion. In addition, two germinal likely pathogenic variants have been identified in the Neurofibromin 1 (NF1) and succinate dehydrogenase complex flavoprotein subunit A (SDHA) genes. Our data suggest a possible additional role of the WAC variant in early tumor development, highlighting the importance of oncogenetic testing in patients with rare neurodevelopmental syndromes and brain tumors.
Keefe AC, Scott AA, Kruidenier L
… +20 more, Conta J, Sternen DL, Candadai SVC, Stasi SM, Parish-Morris J, Sikes M, Adam MP, Beck AE, Hayek JC, Glass I, Bennett JT, Mirzaa G, Kruszka P, Johnson B, McWalter K, Copenheaver D, Friedman B, Bamshad M, Dipple KM, Wenger TL
Am J Med Genet A
· 2026 Jun · PMID 41693637
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Substantial data supports the use of rapid exome and genome sequencing (rES/rGS) in Neonatal Intensive Care Units (NICU), but fewer studies have examined the impact of rES/rGS in other pediatric critical care units. We e...Substantial data supports the use of rapid exome and genome sequencing (rES/rGS) in Neonatal Intensive Care Units (NICU), but fewer studies have examined the impact of rES/rGS in other pediatric critical care units. We evaluated the impact on diagnostic yield and time to diagnosis following a single-center hospital policy change allowing broader, first-line rES/rGS for children in Cardiac and Pediatric Intensive Care Units (CICU, PICU). We conducted retrospective chart review from 1/1/2021-9/15/2024 for children in the CICU and PICU for whom genetic consultation was requested prior to (n = 64) and after (n = 211) the policy change. Exome and genome sequencing (ES/GS), both rapid and non-rapid, was completed in 174 patients, with 146 completing rES/rGS. Overall ES/GS diagnostic yield was 36.5% in the CICU and 31.2% in the PICU. Post-policy change, there were more requested genetics consults, an increase in rES/rGS completed (CICU: 4.8% vs. 56.0%; PICU: 13.6% vs. 88.5%), an increase in diagnoses/year (CICU: 6.0 vs. 14.3; PICU: 6.0 vs. 7.6), and decreased time to diagnosis (CICU: 23 vs. 12 days; PICU: 33 vs. 16 days). We show that changing hospital policy to allow for first-line rES/rGS in the CICU/PICU led to more consults, a higher percentage of patients receiving rES/rGS, a 2.4-fold increase in genetic diagnoses in the CICU, and decreased time to diagnosis in both units.
Connolly C, Parmar HA, Hipp L
… +1 more, Higashimoto T
Am J Med Genet A
· 2026 Jun · PMID 41693634
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FOXA2 (hepatocyte nuclear factor-3β, HNF-3β) encodes a transcriptional activator involved in early embryogenesis, particularly in the patterning and differentiation of midline structures such as the neural tube, foregut,...FOXA2 (hepatocyte nuclear factor-3β, HNF-3β) encodes a transcriptional activator involved in early embryogenesis, particularly in the patterning and differentiation of midline structures such as the neural tube, foregut, and pituitary gland. Its role in human pathogenesis was first suspected when patients with deletion of chromosome 20p11.2 which encompassed the FOXA2 gene were reported. With improvement in molecular diagnosis, patients with variants in FOXA2 genes have more recently been described with pituitary dysfunction, hypoglycemia, craniofacial, and/or endoderm-derived organ malformations; however, they are still rare. Here, we report a family who experienced fetal loss due to multiple congenital anomalies identified with FOXA2 gene, NM_021784.5(FOXA2):c.429C>A (p.Tyr143Ter). Further segregation analysis of this variant identified the presence of the same variant in the father of the fetus, who himself had a history of growth hormone deficiency and pituitary malformation. We report for the first time the varying degrees of severity of disorder most likely attributed to variant in FOXA2 gene within the same family.
Zhang J, Chen S, Dong G
… +4 more, Yang S, Wang P, Zhou Q, Wang P
Am J Med Genet A
· 2026 Jun · PMID 41680094
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To enhance clinicians' understanding of Sifrim-Hitz-Weiss syndrome (SIHIWES), this study investigated the clinical phenotypes, genetic characteristics, and response to growth hormone therapy in a patient. A case of a pat...To enhance clinicians' understanding of Sifrim-Hitz-Weiss syndrome (SIHIWES), this study investigated the clinical phenotypes, genetic characteristics, and response to growth hormone therapy in a patient. A case of a patient with global developmental delay and distinctive facial features is presented. To identify the underlying etiology, peripheral blood samples were collected from the patient and both parents. Whole-exome sequencing (WES) and genomic copy number variation (CNV) analysis were conducted. Candidate variants were confirmed by Sanger sequencing within the family, and bioinformatics tools assessed their pathogenicity. WES identified a de novo heterozygous variant, c.3547C>T (p.Arg1183Cys), in CHD4. Both parents were wild-type at this locus, and CNV analysis revealed no pathogenic variants. Based on ACMG guidelines, this variant is classified as pathogenic. Combining clinical phenotypes with genetic findings, this study confirmed the diagnosis of Sifrim-Hitz-Weiss syndrome. Protein structure modeling indicated that the CHD4 protein harbors an Arg1183Cys variant in the α-helix. The cysteine side chain, containing a sulfur atom, may introduce new chemical interactions, potentially altering CHD4 protein function. Short-term growth-promoting effects were observed with recombinant human growth hormone (rhGH) therapy, providing new insights for managing this disorder. Long-term efficacy and safety should be evaluated in larger studies.
van der Leij M, de Groot E, Orlandini E
… +3 more, Klein WM, Ockeloen CW, Geelen JM
Am J Med Genet A
· 2026 Jun · PMID 41680088
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KBG syndrome is a rare autosomal dominant neurodevelopmental disorder caused by ANKRD11 haploinsufficiency and is characterized by short stature, distinctive facial features, intellectual disability or developmental dela...KBG syndrome is a rare autosomal dominant neurodevelopmental disorder caused by ANKRD11 haploinsufficiency and is characterized by short stature, distinctive facial features, intellectual disability or developmental delay, congenital anomalies and skeletal anomalies. Although skeletal anomalies are reported in about 75% of cases, their nature and extent in relation to growth are largely unknown. Therefore, this study aims to asses the prevalence of skeletal anomalies in KBG syndrome and explore whether there is a relationship with short stature. This retrospective cohort study includes patients with a confirmed diagnosis of KBG syndrome, with available radiographic images at the Radboud University Medical Center. The radiographs were re-evaluated by a radiologist focusing on the presence of spinal, costal, vertebral, and hand anomalies using standardized radiological criteria. In our cohort of 38 persons with KBG syndrome, 92% show skeletal anomalies on radiographic imaging. The most frequent observations on the radiographs were spinal anomalies (74%) and costal anomalies (40%). Specifically, lordosis (36%) had the highest prevalence. Patients with short stature (n = 14) showed higher prevalences of kyphosis and delayed skeletal age. In conclusion, this study demonstrates a high prevalence and broad variety of skeletal anomalies in individuals with KBG syndrome.
Am J Med Genet A
· 2026 Jun · PMID 41674207
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Poikiloderma with neutropenia (PN) is a rare autosomal recessive disorder characterized by poikiloderma, neutropenia, and recurrent infections. We present a patient with PN carrying a novel homozygous pathogenic variant...Poikiloderma with neutropenia (PN) is a rare autosomal recessive disorder characterized by poikiloderma, neutropenia, and recurrent infections. We present a patient with PN carrying a novel homozygous pathogenic variant in the USB1 gene (c.547delC, p.Leu183Trpfs82*), and reviewed 90 PN cases reported since 1991 (including one new case) in order to assess genotype-phenotype correlations. Early symptoms included erythematous rash and recurrent infections (44% and 27% at 6 months, respectively), poikiloderma (88% at 12 months), and hepatosplenomegaly or elevated liver enzymes (22% at 12 months). Photosensitivity (21%) had a median onset at 21 months. Nail dystrophy and palmoplantar hyperkeratosis emerged later (36-48 months). Growth delay occurred in 53%, and 54% showed dental anomalies such as caries, hypodontia, or peg-shaped teeth. Notably, 17% developed malignancies-four non-melanoma skin cancers and 11 hematologic malignancies (AML, MDS, or pre-MDS), highlighting a significant oncogenic risk. Genetic analysis revealed 34 different pathogenic variants in the USB1 gene. Our findings underscore the importance of early recognition and long-term cancer surveillance in PN patients and provide a foundation for further research into USB1's role and the disorder's progression.
Nordenskjöld A, Alm S, Eisfeldt J
… +7 more, Cao J, Anderberg M, Barker G, Matsson H, Holmdahl G, Lindstrand A, Lagerstedt-Robinson K
Am J Med Genet A
· 2026 Jun · PMID 41668247
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Bladder exstrophy and epispadias complex (BEEC) is one of the most severe congenital malformations of the urogenital tract, significantly impacting continence, sexual function, and renal function. To date, the only recur...Bladder exstrophy and epispadias complex (BEEC) is one of the most severe congenital malformations of the urogenital tract, significantly impacting continence, sexual function, and renal function. To date, the only recurrent genetic aberration identified is the 22q.11.2 microduplication, but several candidate regions and genes including components of the WNT signaling pathway have been proposed. This study aimed to identify additional genes contributing to the pathogenesis of BEEC and to verify previously suggested candidate genes. We performed trio-based whole genome sequencing on 19 individuals with BEEC and their unaffected parents; of those, five carried earlier reported microdeletions. The genome data was also filtered in silico for variants in 204 candidate genes selected from databases, publications, and in-house findings. Variants were prioritized based on allele frequency and predicted functional impact. In 8 of the 19 trios, our findings highlight members of the ADGR-gene family as novel candidate genes for BEEC, alongside other implicated genes such as TRANK1, CSNK1E, IFT122, SDK1, SDK2, and KIF19 and propose two more CNVs as risk factors for BEEC; on chromosome regions 1p36 and 16p11.2. This study identifies novel candidate genes for BEEC within the ADGR gene family. The results also further implicate a complex molecular background of BEEC.
Mosera M, Stover S, Boos E
… +13 more, Casey M, Fanning J, Fechter C, Grace M, Hatch LD, Ibach M, Jackson C, Liang J, Mann C, Morris EA, Turnbull J, Williams M, Schuler BA
Am J Med Genet A
· 2026 Jun · PMID 41656515
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Genetic contributors to perinatal demise are common but frequently undiagnosed due to clinical and logistical barriers. We aimed to improve access to genetic for intrauterine fetal demise (IUFD), stillbirth, and early ne...Genetic contributors to perinatal demise are common but frequently undiagnosed due to clinical and logistical barriers. We aimed to improve access to genetic for intrauterine fetal demise (IUFD), stillbirth, and early neonatal death by developing a multidisciplinary workflow. A working group representing clinical genetics, maternal-fetal medicine, neonatology, pathology, obstetrics, palliative care, laboratories, and health information technology identified barriers and designed solutions for genetic testing in perinatal demise. Tools developed included testing algorithms, specimen collection and handling guides, documentation templates, and electronic health record integration. Case reviews and stakeholder feedback informed iterative refinement. The workflow clarified team roles, timing, and coordination across specialties. Scenario-specific algorithms for stillbirth, neonatal demise, and pediatric genetics consultations guided testing decisions. A specimen-testing matrix linked sample types with available tests and laboratories. Implementation was supported by education and centralized resources. Representative cases demonstrated improved sample collection, diagnostic yield, and family counseling through early communication and defined responsibilities. A multidisciplinary workflow improved the feasibility and consistency of genetic evaluation in perinatal demise. This model may guide other institutions seeking to implement or enhance genetic testing processes for families affected by pregnancy loss or neonatal death.
Yue SL, Pillai RLI, Frazier Z
… +12 more, Osika H, Quinn M, O'Toole J, Heslin B, Zhang B, Dies KA, Pais L, O'Donnell-Luria A, Horlbeck MA, Kossowsky J, Lipton J, Srivastava S
Am J Med Genet A
· 2026 Jun · PMID 41652658
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The early developmental profile of Kleefstra syndrome remains undercharacterized. To address this gap, this study investigated a large clinical cohort of patients with Kleefstra syndrome, characterizing age of achievemen...The early developmental profile of Kleefstra syndrome remains undercharacterized. To address this gap, this study investigated a large clinical cohort of patients with Kleefstra syndrome, characterizing age of achievement of infant/toddler developmental milestones and quantifying language and visual motor developmental quotients (DQs) using the Capute Scales developmental screening tool. We conducted a retrospective chart review on individuals with molecularly confirmed Kleefstra syndrome. We reported age of achievement of motor and language milestones. In a subset of this cohort, we evaluated DQs for language and visual motor skills based on the Capute Scales. Among 100 individuals (43 males, 57 females; median age 9 years), rolling occurred at a median of 6 months, sitting at 10 months, independent walking at 1.96 years, and first words at 24 months. Capute Scales testing (n = 24) showed median DQs as follows: visual motor skills (53, IQR = 42-71), overall language (56, IQR = 42-67), expressive language (52, IQR = 35-60), and receptive language (50, IQR = 42-61). This work quantifies the early developmental profile of Kleefstra syndrome and suggests that developmental delay can be significant from an early age, making early initiation of services such as physical therapy, occupational therapy, and speech therapy crucial to ensuring optimal skills development. This cross-sectional analysis highlights the need for incorporating longitudinal developmental assessments into the clinical care of patients with Kleefstra syndrome-particularly during infancy and early childhood-to ensure that appropriate educational supports are in place.
Am J Med Genet A
· 2026 Jun · PMID 41651789
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The ciliopathies are a group of genetic disorders caused by defective function of either the primary cilia (a large number) or the motile cilia (a much smaller number). These have been defined as diseases with mutations...The ciliopathies are a group of genetic disorders caused by defective function of either the primary cilia (a large number) or the motile cilia (a much smaller number). These have been defined as diseases with mutations in genes encoding individual ciliary or cilia-associated proteins. Recently, it has become apparent that the composition of the ciliary membrane influences its function. For instance, the ciliary membrane contains more cholesterol than other regions of the cell membrane and a variety of unique receptors and ion channels. Additionally, it appears that primary cilia have evolved to lower the threshold for activating signal transduction by establishing the environment essential for signaling pathways on a limited portion of the cell surface. By positioning receptors and downstream signaling components in this thin protrusion at a precise time and location within the plasma membrane, the cell can better orient its physiological response to external stimuli. Cholesterol deficiency can alter cilia formation and function with effects on Sonic hedgehog signaling. In this review, we discuss these new concepts and apply them to the developmental disorder Smith-Lemli-Opitz syndrome and the developmental and neurodegenerative disorder Niemann-Pick C disease, demonstrating that they are also ciliopathies.
Théberge ET, Sun B, Wang R
… +7 more, Mohajeri A, Van Karnebeek CDM, Boerkoel CF, Huynh S, Horvath G, Chen SRW, Lehman A
Am J Med Genet A
· 2026 Jun · PMID 41649386
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The 1,4,5-trisphosphate receptor type 1 (ITPR1) gene encodes an endoplasmic reticulum calcium release channel, in which loss-of-function mutations have been associated with spinocerebellar ataxias and related neurologica...The 1,4,5-trisphosphate receptor type 1 (ITPR1) gene encodes an endoplasmic reticulum calcium release channel, in which loss-of-function mutations have been associated with spinocerebellar ataxias and related neurological phenotypes. Only one gain-of-function mutation in the highly conserved suppressor domain of ITPR1 has been previously reported. We report a novel de novo ITPR1 variant (p.(Tyr131His)) detected by whole genome sequencing in a child with an unexplained movement disorder, characterized by tremor and dystonia, concurrent with a second diagnosis of Myhre syndrome. The proband's movement disorder characteristics share much overlap with previously reported individuals with suppressor domain variants; however, she does not have ataxia. We provide functional evidence of this variant's gain-of-function consequence via in vitro experiments of inositol 1,4,5-triphosphate-mediated calcium release. Our findings deepen the knowledge of ITPR1-mediated movement disorders, expanding the phenotypic spectrum to include movement disorders without ataxia.
Kaur R, Chowdhury MR, Chauhan S
… +5 more, Gupta N, Kumar A, Sapra S, Saranya S D, Kabra M
Am J Med Genet A
· 2026 Jun · PMID 41641655
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Neurofibromatosis type 1 (NF1) is a complex multisystem disorder with marked phenotypic heterogeneity and variable expressivity. While its clinical features have been extensively documented in Western populations, data f...Neurofibromatosis type 1 (NF1) is a complex multisystem disorder with marked phenotypic heterogeneity and variable expressivity. While its clinical features have been extensively documented in Western populations, data from India remain limited and largely based on smaller cohorts. This study provides a comprehensive description of the NF1 phenotype in an Indian cohort of 72 patients. The study also explored the frequency of NF1 deletions/duplications in NF1 and their contribution to clinical variability. This cohort adds to the limited Indian data on NF1 and highlights the need for molecular testing in routine clinical evaluation. These findings emphasize the importance of region-specific phenotypic profiling and support the integration of genetic insights into individualized patient care.