Dystroglycanopathies arise when α-dystroglycan, a membrane protein that anchors muscle fibers to their surrounding basement membrane, is not properly decorated with sugar chains. At least 19 causative genes have been identified to date, reflecting the complexity of the glycosylation pathway that builds and attaches these critical sugar modifications. One of these genes is CRPPA, formerly known as ISPD, which encodes CDP-L-ribitol pyrophosphorylase A. This enzyme synthesizes CDP-ribitol, a substrate that downstream glycosyltransferases require to attach ribitol phosphate groups to α-dystroglycan. When that enzymatic step fails, dystroglycan loses its ability to bind ligands and interact with the basement membrane, destabilizing the muscle membrane and paving the way for progressive degeneration.

Variants in CRPPA produce a spectrum of disease severity. At the severe end sit congenital muscular dystrophies, often accompanied by brain and eye abnormalities such as cerebellar hypoplasia, ocular defects, and developmental delay. At the milder end lies limb-girdle muscular dystrophy, a clinically diverse group of disorders with an estimated prevalence of roughly 2 per 100,000 people, characterized by progressive proximal weakness and dystrophic features on muscle biopsy, typically emerging in late childhood, adolescence, or adulthood. Most reported individuals with CRPPA-related disease, however, manifest symptoms in infancy or early childhood, frequently with additional systemic or neurodevelopmental involvement. Although biallelic single-nucleotide variants in CRPPA are well documented, only a handful of reports describe compound heterozygous genotypes that combine a single-nucleotide variant with a copy number variant, and the phenotypic consequences of such combinations remain incompletely understood.

The diagnostic journey began with whole exome sequencing of the proband at the Kariminejad-Najmabadi Pathology and Genetics Center. Genomic DNA extracted from peripheral blood was enriched using the Twist Exome V2.0 kit and sequenced on an Illumina NovaSeq 6000 platform, with reads aligned to the GRCh38 reference genome. Variant annotation and classification followed American College of Medical Genetics and Genomics guidelines. Two heterozygous variants emerged in CRPPA: a missense single-nucleotide variant, c.267G>C, which substitutes cysteine for tryptophan at residue 89 (p.Trp89Cys), and a gross deletion spanning approximately 641 kilobases of chromosome 7p21.2 that removes exons 9 and 10 of the gene, along with neighboring genes including MEOX2 and several antisense transcripts.

Neither variant had been seen before in population databases. The missense variant was absent from the Genome Aggregation Database v4.1 and from Iranome, an Iranian genomic population database, and multiple in silico prediction tools, including PolyPhen-2, MutationTaster, CADD, FATHMM, REVEL, and PrimateAI, consistently flagged it as deleterious. CADD assigned it a score of 29.7, and REVEL returned a supporting score of 0.75. Nevertheless, because direct functional evidence was lacking, the variant was classified as a variant of uncertain significance under ACMG recommendations, supported by criteria PM2, PP3, and PP1. The deletion, absent from the Database of Genomic Variants and never previously reported, was classified as likely pathogenic based on its size, gene content, and segregation data.

Structural modeling added mechanistic texture to these predictions. AlphaFold2 localized residue Trp89 to a highly conserved region within the N-terminal catalytic domain of the enzyme, immediately adjacent to a β-strand, with very high prediction confidence, indicated by a per-residue confidence score above 90. The HOPE server predicted that replacing the bulky tryptophan side chain with the smaller cysteine would leave an empty space within the protein core, potentially reducing local structural stability and disrupting important domain contacts. Because the N-terminal catalytic domain houses the enzyme’s active-site machinery, missense variants in this region may compromise the integrity of the site that synthesizes CDP-ribitol. The authors caution, however, that functional studies will be required to confirm the biological significance of these computational findings.

Sanger sequencing and array comparative genomic hybridization traced the inheritance pattern through the family. The affected sister carried both variants, consistent with a compound heterozygous state. The missense variant was absent from the mother, while array-CGH confirmed that the mother carried the 641-kilobase deletion, meaning each parent contributed one defective allele. The proband’s clinical picture fit the limb-girdle pattern: progressive proximal lower limb weakness beginning at 41, elevated serum creatine kinase at 1193 units per liter against a normal range of 24 to 195, and electromyography showing features of a chronic non-irritable myopathy. Neurological examination revealed no calf hypertrophy, scapular winging, or joint hypermobility, and no ocular or central nervous system involvement was observed, with normal cognition.

His sister’s course, despite the identical genotype, diverged sharply. She developed symptoms at approximately 10 years of age, with progressive proximal weakness involving both upper and lower limbs. Her serum creatine kinase was only mildly elevated at 460 units per liter, notably lower than her brother’s, and her muscle biopsy revealed dystrophic changes consistent with a myopathic process. Her electromyography findings were comparable to her brother’s, showing chronic non-irritable myopathy, and she too had no evidence of brain or eye involvement and normal cognitive function. Where the brother’s weakness was restricted to the proximal lower limbs, hers spanned both limb girdles. Both siblings received supportive metabolic therapy with coenzyme Q10, riboflavin, and L-carnitine, and at follow-up the proband demonstrated only mild proximal lower limb weakness.

To place the family in context, the researchers reviewed published studies from 2012 through 2026 reporting CRPPA variants with sufficient clinical information. Among 59 patients, the majority, 37 patients or 62.7 percent, were compound heterozygous, while 20 patients, or 33.9 percent, carried homozygous variants, and in two patients only a single identifiable CRPPA allele was reported. Pathogenic variants were distributed throughout the coding region, but exon 9 emerged as a recurrent site of variation, underscoring its functional importance. The Human Gene Mutation Database currently lists 54 disease-associated CRPPA variants, with missense variants predominating and gross deletions forming a smaller proportion. Reported deletions most frequently involve exon 9 and less commonly extend to exon 10, and most published cases carrying such deletions presented with severe congenital dystroglycanopathy accompanied by cerebellar hypoplasia, ocular abnormalities, and developmental delay.

Milder phenotypes, however, have also been described, particularly when exon-level deletions occur in compound heterozygosity with missense variants. One recent report described a patient carrying a deletion involving exons 6 through 9 who presented with a limb-girdle phenotype accompanied by cerebellar and brainstem hypoplasia and cardiac involvement. Although genotype-phenotype correlations remain incompletely defined, previous studies suggest that specific compound heterozygous genotypes, particularly those involving frameshift or truncating variants, may lead to early-onset severe disease, whereas other combinations can produce later-onset, milder limb-girdle presentations. This variability is likely related to differing degrees of residual protein function. In the present family, the combination of the novel p.Trp89Cys variant and the exon 9-10 deletion is consistent with, although it does not prove, a hypomorphic disease mechanism in which partial enzyme activity survives.

The age at onset of 41 years in the male proband is markedly later than that reported in most CRPPA-related limb-girdle cases, broadening the known age-of-onset spectrum of the disease. Because most reported cases are childhood-onset and severe, the authors suggest that milder adult-onset presentations may be underrecognized, meaning some adults with unexplained proximal weakness could be carrying undiagnosed CRPPA-related disease. The finding carries a practical message for clinicians: this diagnosis should be considered even in adult-onset proximal muscle weakness that lacks the brain or eye abnormalities typically associated with more severe dystroglycanopathy phenotypes. It also underscores the importance of comprehensive genetic evaluation that assesses both single-nucleotide and copy number variants, since exome sequencing alone would have missed the gross deletion that completed the compound heterozygous genotype.

Beyond its diagnostic implications, the family demonstrates marked intrafamilial phenotypic variability within a single CRPPA-affected household, with childhood and late-onset presentations arising from the same compound heterozygous genotype. What determines whether one sibling loses substantial muscle function in childhood while another remains symptom-free into middle age remains an open question that current genetic testing cannot fully answer. For now, the case expands the mutational and clinical spectrum of CRPPA-related disease and adds a compelling data point to the ongoing effort to untangle the genotype-phenotype relationships of the dystroglycanopathies, a task made harder by the sheer diversity of the glycosylation pathway that keeps muscle membranes anchored and intact.

Subject of Research: Genetics of CRPPA-related limb-girdle muscular dystrophy and intrafamilial phenotypic variability

Article Title: Variable Phenotypic Manifestations of Novel Compound Heterozygous CRPPA Variants in Two Iranian Siblings With Limb‐Girdle Muscular Dystrophy

Article References: Alagha, P., Ahangari, F., Kariminejad, A., Ghasemi, A., Gholami, S., Sadatian, N., Kariminejad, R., Kahrizi, K., Okhovat, A. A., & Najmabadi, H. (2026). Variable Phenotypic Manifestations of Novel Compound Heterozygous CRPPA Variants in Two Iranian Siblings With Limb‐Girdle Muscular Dystrophy. Molecular Genetics & Genomic Medicine, 14(10), Article e70312. https://doi.org/10.1002/mgg3.70312

Image Credits: AI Generated

DOI: 10.1002/mgg3.70312

Keywords: CRPPA, limb-girdle muscular dystrophy, dystroglycanopathy, alpha-dystroglycan, compound heterozygous, copy number variant, missense variant, whole exome sequencing, phenotypic variability, genotype-phenotype correlation, Iranian siblings, muscular dystrophy

The 16p13.11 region is a genomic trouble spot. It is packed with low-copy repeats, segments of DNA that are nearly identical in sequence and sit in repeating blocks along the chromosome. During DNA replication and repair, these near-identical sequences can misalign, and when the cellular machinery recombines the wrong pair, chunks of the genome are deleted or duplicated. This process, called non-allelic homologous recombination, makes 16p13.11 a recurrent hotspot for copy number variants, the gains and losses of DNA segments that underlie a family of genomic disorders. Duplications and deletions in this region have been linked in the medical literature to developmental delay, intellectual disability, language impairment, behavioral abnormalities, attention-deficit/hyperactivity disorder, autism spectrum disorder, distinctive facial features, and cardiovascular anomalies.

What makes 16p13.11 microduplication so difficult is that it does not behave like a classic disease-causing mutation. Many carriers are apparently healthy adults, and the duplication is frequently inherited from a parent who shows no signs of any related condition. Geneticists describe such variants as having incomplete penetrance, meaning not everyone who carries the extra DNA shows effects, and variable expressivity, meaning those who are affected can show very different symptoms. In 2024, the Clinical Genome Resource assigned the region a triplosensitivity score of 2, a rating that suggests moderate but not definitive pathogenic potential when an extra copy is present.

The Wenzhou team used chromosomal microarray analysis, a technique recommended by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine for prenatal diagnosis, to scan fetal DNA extracted from uncultured amniotic fluid cells. The platform they used, the CytoScan 750K array, detects copy number changes across the whole genome at high resolution. The 19 duplications they found ranged in size from 0.80 to 1.60 megabases and spanned between 7 and 13 genes cataloged in the Online Mendelian Inheritance in Man database. Every duplicated segment overlapped the critical region associated with 16p13.11 microduplication syndrome, and all coordinates were mapped against the hg19 reference genome.

The reasons the pregnancies reached amniocentesis in the first place were varied and mostly unrelated to the duplication itself. Seven cases were prompted by advanced maternal age, five by a history of adverse pregnancy outcomes, three by high-risk serum screening results, and four by abnormal ultrasound findings. Those four ultrasound cases were strikingly heterogeneous. One fetus had increased nuchal translucency, a thickening of the fluid-filled space at the back of the neck. Another showed a constellation of severe problems: growth lagging about three weeks behind dates, fluid accumulating in both the chest and abdomen, an enlarged heart, and tricuspid regurgitation. A third displayed right upper limb anomalies consistent with radial dysplasia, including a short, curved ulna, an extremely short radius, and marked angling of the wrist. The fourth had a single umbilical artery and an echogenic intracardiac focus in the left ventricle, a bright spot on the heart that is usually benign.

Pedigree analysis, in which both parents are tested to determine whether the duplication was inherited or arose newly in the fetus, was completed in only five of the 19 cases. In four of those five, the duplication came from a phenotypically normal mother or father; one was de novo, appearing for the first time in the child. Notably, after comprehensive genetic counseling, the parents of all five fetuses with confirmed inheritance information chose to continue their pregnancies, a decision the authors emphasize reflects individual family choices rather than a general recommendation.

The pregnancy outcomes and follow-up data form the heart of the study. Three couples, all counseled by multidisciplinary teams, elected to terminate their pregnancies, including two of the cases with severe multi-organ ultrasound abnormalities. The remaining 16 fetuses were carried to term, and postnatal follow-up was ultimately available for 14 children ranging in age from 10 months to 10 years. The picture that emerged was largely reassuring. Five children were reported to be developing ahead of their age-matched peers, and seven showed no abnormalities at all according to their parents. One child, now nine years old, showed delayed development: walking began at 17 months and first words did not arrive until age three, with parents describing average expressive language ability. One infant was hospitalized at birth because of a ventricular septal defect, a hole in the wall separating the heart’s lower chambers, but subsequent examinations revealed no additional problems. Two children were lost to follow-up.

The authors are careful about what these outcomes do and do not prove. The child with developmental delay carried a 1.25 megabase duplication spanning ten genes, including NDE1, a gene with established roles in neurogenesis and the development of the cerebral cortex. That association fits the neurodevelopmental spectrum described for 16p13.11 imbalances. Yet other children in the same cohort carried duplications of similar size or gene content and developed normally, which demonstrates that duplication size and gene count alone cannot predict how any individual child will fare. The region also contains ABCC6, whose loss-of-function variants cause abnormal tissue mineralization, and MYH11, which is involved in smooth muscle and has been linked to cardiovascular disease, but the study found no evidence that extra copies of these genes directly caused the observed heart defect. Background genetic modifiers probably contribute to the variability, though their individual effects remain beyond the reach of this data set.

For prenatal counselors, the practical message is one of calibrated uncertainty. The researchers argue that 16p13.11 microduplication should be presented to expectant parents neither as a benign curiosity nor as a definite diagnosis, but as a susceptibility variant with reduced penetrance and variable expressivity. Interpretation should weave together the fetal ultrasound picture, the characteristics of the duplication itself, parental testing results where available, and family history. An inherited duplication from a healthy parent is somewhat reassuring but does not eliminate risk, while a de novo duplication or one accompanied by significant structural abnormalities warrants a broader discussion of possible outcomes. After birth, the authors recommend surveillance guided by the child’s clinical course rather than the laboratory result: close monitoring of speech and motor milestones, attention to learning and behavioral concerns as the child grows, and cardiac review when indicated, since some effects may only surface later in childhood or adulthood.

The study’s limitations are acknowledged candidly. It was retrospective and single-center, the number of cases was small, parental testing was not systematically performed, and developmental outcomes relied mainly on telephone interviews and parental reports rather than standardized assessments for every child. For the terminated pregnancies, no systematic fetal autopsy or additional genetic testing was carried out, so other causes of the severe ultrasound findings cannot be excluded. Even so, the results align with recent prenatal series from other Chinese centers, which similarly found that most live-born children with the duplication showed no major abnormalities in early follow-up while a minority experienced neurodevelopmental or cardiac problems. Taken together, the evidence supports treating 16p13.11 microduplication as a finding to be understood, monitored, and discussed honestly, not feared automatically, and it underscores how much modern prenatal genetics still depends on long-term follow-up to turn raw copy number calls into meaningful guidance for families.

Subject of Research: Prenatal detection and postnatal outcomes of 16p13.11 microduplication identified by chromosomal microarray in a large pregnancy cohort

Article Title: Prenatal Diagnosis and Postnatal Follow‐Up of 19 Fetuses With 16p13.11 Microduplication in a Cohort of 12,038 Pregnancies From South Zhejiang

Article References: Lv, X., Li, S., Zhou, L., Wang, R., Yu, Y., Xu, C., Xu, X., Tang, X., & Li, H. (2026). Prenatal Diagnosis and Postnatal Follow‐Up of 19 Fetuses With 16p13.11 Microduplication in a Cohort of 12,038 Pregnancies From South Zhejiang. Molecular Genetics & Genomic Medicine, 14(10), Article e70324. https://doi.org/10.1002/mgg3.70324

Image Credits: AI Generated

DOI: 10.1002/mgg3.70324

Keywords: 16p13.11 microduplication, chromosomal microarray analysis, copy number variant, prenatal diagnosis, incomplete penetrance, genetic counseling, developmental delay, ventricular septal defect, low-copy repeats, NDE1, amniocentesis, genotype-phenotype correlation

The technical premise rests on normative modeling, a statistical framework that has become one of the most influential tools in modern neuroimaging. Instead of comparing patients with a small control group and asking whether a brain region is, on average, larger or smaller, normative modeling fits reference curves — much like the growth charts pediatricians use for height and weight — that describe the expected range of brain measures at every age. Each individual scan is then assigned a centile, or deviation score, quantifying how far that person’s brain structure sits from the population norm. Applied to thousands of scans, this approach turns a single clinical MRI into a rich phenotypic fingerprint, one that can flag extreme deviations and map where in the brain they concentrate.

What makes the new work distinctive is its source of data. Prospective neuroimaging studies routinely exclude individuals with severe cognitive impairment, significant medical comorbidities, or an inability to tolerate a research MRI session without sedation — features that are common in 22q11.2 deletion syndrome and other rare genetic disorders. Those exclusions quietly narrow the phenotypic spectrum that research cohorts can see, limiting how generalizable the findings are to the full population of affected patients. Clinical scans, by contrast, are acquired for medical reasons and include precisely the patients that research studies tend to leave out. In this retrospective, cross-sectional study, the team analyzed 92 patients with 22q11.2 deletion syndrome, aged six months to 21 years and 49 percent female, alongside 252 matched clinical controls, all drawn from hospital records at the Children’s Hospital of Philadelphia.

The reference curves themselves were derived from 1,995 clinical scans, a large normative sample that allowed the researchers to estimate age-specific expectations for a battery of structural brain measures: total gray matter volume, white matter volume, subcortical gray matter volumes, intracranial volume, cortical thickness, and regional cortical surface area and volume. The statistical machinery behind these charts, generalized additive models for location, scale, and shape, is the same family of models used to construct conventional child growth standards, and it can capture how both the average and the variability of brain measures change across development. Every patient scan was then scored against these population norms, producing deviation maps that could be compared across individuals and aggregated to characterize the syndrome as a whole.

The headline result is a picture of widespread structural reduction. Patients with 22q11.2 deletion syndrome showed broad decreases in brain volumes, with the largest effect reaching a Cohen’s d of −1.31 — a very large effect size by any neuroimaging standard — and reductions in cortical surface area peaking at d = −0.71. Cortical thickness, however, moved in the opposite direction, increasing to d = 0.39. That combination is technically meaningful: reduced surface area with preserved or increased thickness suggests that the cortex in this syndrome is affected in its areal expansion rather than simply being thinned, a dissociation that implicates specific developmental processes in the folding and areal patterning of the cerebral sheet. Subcortical structures and white matter were also reduced, consistent with the syndrome’s known impact on deep gray matter nuclei and connecting pathways.

Because clinical samples invite skepticism about scan quality and processing, the team validated their findings against an entirely independent source: the ENIGMA-22q research consortium, a multinational collaboration that has assembled prospectively collected research MRI data from 22q11.2 deletion syndrome patients across dozens of sites. The spatial convergence was striking. Regional patterns of volume and surface area deviations in the clinical cohort correlated with those in the research cohort at r = 0.61 to 0.87, indicating that the two approaches — one built on routine hospital scans, the other on carefully standardized research acquisitions — were seeing the same underlying biology. This is a critical proof of principle that heterogeneous clinical imaging, processed with appropriate quality controls, can robustly characterize brain structure in rare genetic disorders at a scale and inclusiveness that research cohorts alone cannot match.

Within-syndrome heterogeneity emerged as a central theme. Forty percent of patients showed at least one global brain measure below the 2.5th centile of the population norm — a rate of extreme deviation far exceeding what would be expected by chance — yet individual patients varied enormously in which measures were affected and how severely. Standard growth charts, the authors note, can identify patients who deviate from typical development, but they cannot distinguish a patient whose brain is small because of the syndrome from one who is disproportionately affected relative to their genetic peers. That distinction matters clinically, because the patients who sit at the extreme tail of their own syndrome’s distribution may face different risks and may need different monitoring than those who cluster near the syndrome’s average.

To address that gap, the team generated syndrome-specific growth charts — reference curves built from the 22q11.2 deletion syndrome patients themselves, so that each patient’s brain measures could be scored against the expectations of their genetic peers rather than the general population. In exploratory analyses, deviations in cerebellar volume relative to other 22q11.2 deletion syndrome patients were nominally associated with lower language scores across two independent assessment methods, the Clinical Evaluation of Language Fundamentals and the Preschool Language Scales, with p-values below 0.03. The cerebellum, long appreciated for its role in motor coordination, has increasingly been implicated in language and cognition, and the finding hints that cerebellar development may carry prognostic information about cognitive and linguistic outcomes in this syndrome. The authors are careful to frame these analyses as exploratory, but the framework they introduce — scoring individual brain structure against syndrome-specific norms and testing whether those scores predict outcomes — is a novel route toward risk stratification in rare neurogenetic conditions.

The study also reached back to the genome itself. Spatial patterns of cortical volume and surface area deviation across the cortex correlated with the expression of genes located within the 22q11.2 locus, as mapped by the Allen Human Brain Atlas, a publicly available resource that charts where thousands of genes are expressed across the human brain. This gene-expression alignment suggests that the regional pattern of brain alteration is not random but reflects, at least in part, the spatial distribution of the very genes whose absence defines the syndrome. It is a technically elegant convergence: the deletion removes a set of genes, those genes are expressed unevenly across the cortex, and the cortex deviates unevenly in exactly the regions where the deleted genes are most active.

The implications extend well beyond a single microdeletion. 22q11.2 deletion syndrome affects an estimated one in roughly 2,000 to 4,000 births and is among the most common copy number variants involving the brain, and its study has long served as a model for understanding how CNVs shape neuropsychiatric risk, including schizophrenia, autism spectrum disorders, and attention-deficit/hyperactivity disorder. If routine clinical MRI can be transformed into syndrome-specific brain charts for this condition, the same pipeline — normative modeling from large clinical reference samples, deviation scoring, validation against research consortia, and linkage to cognitive outcomes — could in principle be applied to other rare genetic disorders whose patients are systematically underrepresented in research imaging. The work, funded by the National Institute of Mental Health, was conducted under ethical review at CHOP and Penn, with retrospective use of clinical scans determined exempt because it involved secondary use of existing data with low risk to human subjects. What the study delivers, above all, is a scalable framework: a way to turn the scans hospitals already acquire into quantitative, individualized maps of brain development that can include the very patients research studies have historically left behind.

Subject of Research: Brain structure in 22q11.2 deletion syndrome mapped with clinical neuroimaging and normative modeling

Article Title: Charting brain structure in 22q11.2 deletion syndrome with clinical neuroimaging

Article References: Jung, B., Schmitt, J. E., Seidlitz, J., Schabdach, J. M., Karandikar, S., Crowley, T. B., Dorfschmidt, L., Mandal, A. S., Zimmerman, D., Williams, R. M. S., Prem, S., Levitis, E., Gardner, M., Cyr, K., Padmanabhan, V., Taylor, J. H., Ruparel, K., Boen, R., Bearden, C. E., … O’Hara, R. (2026). Charting brain structure in 22q11.2 deletion syndrome with clinical neuroimaging. Genome Medicine. https://doi.org/10.1186/s13073-026-01788-7

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01788-7

Keywords: 22q11.2 deletion syndrome, normative modeling, clinical neuroimaging, ENIGMA-22q, Genome Medicine, brain growth charts, schizophrenia risk, copy number variant, Charting, brain, structure, deletion

Smith-Magenis syndrome affects roughly one in 15,000 to 25,000 births and is caused in most cases by a heterozygous deletion of chromosome band 17p11.2 that includes RAI1, a gene whose dosage is critical for normal brain development. A smaller fraction of patients instead carry a point mutation within RAI1 itself. The classic phenotype, which includes self-hugging, sleep disruption driven by an inverted melatonin rhythm, self-injurious behavior, and intellectual disability, typically crystallizes only after the first year or two of life. In an infant, before the behavioral fingerprint emerges, the diagnosis is notoriously easy to miss, and the syndrome can hide behind a scatter of unconnected problems.

That is precisely what happened here. The boy had been born by cesarean section at 35 weeks and five days, weighed 2,700 grams, and scored a perfect 10 on his Apgar assessments, giving no clue of what was coming. Yet his newborn heel-prick screen came back suspicious: thyroid-stimulating hormone was elevated at 8.58 micro-international units per milliliter while free thyroxine was low at 5.71 picomoles per liter, a biochemical signature of congenital hypothyroidism. Levothyroxine was started promptly, a decision that would later prove critical, because untreated thyroid deficiency in infancy compounds the neurodevelopmental damage caused by an underlying genetic disorder.

In February 2025, at around seven months of age, the boy was hospitalized elsewhere with a urinary tract infection complicated by sepsis. The numbers were alarming: a white blood cell count of 21.46 billion per liter, C-reactive protein of 120.6 milligrams per liter, procalcitonin of 10.2 nanograms per milliliter, and elevated lactate. Imaging revealed bilateral hydronephrosis with dilated ureters, meaning both kidneys were swollen with backed-up urine. He recovered after treatment with meropenem and piperacillin/tazobactam, but the family interrupted his levothyroxine in early April, setting the stage for the thyroid dysfunction to resurface at his next admission.

When he returned to Wuxi in May 2025 with fever, chills, and pyuria, the clinical team assembled a comprehensive picture. Physical examination showed a square face, a mildly depressed nasal bridge, left strabismus, eversion of the upper lip, abnormally short fingers on both hands, generalized low muscle tone, early closure of the anterior fontanel, a short penis, and phimosis. He could not yet sit steadily or crawl, and his language and fine motor skills lagged behind. Urinary injury markers were striking: alpha1-microglobulin at 96.80 milligrams per liter against a reference ceiling of 12.5, microalbumin at 70.70 milligrams per liter, and immunoglobulin G at 24.40 milligrams per liter, all pointing to kidney tubular and glomerular stress.

The urologic workup delivered the headline finding. Voiding cystourethrography, in which contrast dye is instilled into the bladder and tracked under X-ray while the child voids, demonstrated bilateral grade IV vesicoureteral reflux, the second-highest severity on a five-point scale, meaning urine was surging backwards from the bladder up dilated ureters into the renal pelvis on both sides. Static DMSA scintigraphy revealed focal cortical defects in the upper and lower poles of the right kidney, a sign of scarring or impaired perfusion. Dynamic DTPA scintigraphy quantified the damage: effective renal plasma flow measured 180.33 milliliters per minute in the left kidney and 133.77 milliliters per minute in the right, a split function of 57.4 percent versus 42.6 percent that documented early, asymmetric right renal compromise.

To explain the syndromic pattern, the team turned to trio whole-exome sequencing with copy-number-variant analysis, comparing the child’s genome against both parents’. The test found the smoking gun: a heterozygous deletion spanning positions 16,692,403 to 20,321,263 on chromosome 17, roughly 3.63 megabases, encompassing RAI1 and the Smith-Magenis critical region, present in the child but in neither parent. Under ACMG/AMP and ACMG/ClinGen classification standards the deletion was deemed pathogenic, formally establishing the diagnosis. The sequencing also surfaced a maternally inherited heterozygous DUOX2 variant, c.2635G>A (p.Glu879Lys), classified as likely pathogenic. DUOX2 encodes an enzyme essential for thyroid hormone synthesis, so the variant is an intriguing candidate for the boy’s hypothyroidism, but the authors are careful: without functional validation, and with no evidence of overt thyroid disease in the mother, its contribution remains unproven, and a clinically silent carrier state cannot be excluded. Two additional heterozygous variants in CCBE1 and RAG2 were flagged as uncertain significance and do not explain the phenotype.

The genetics here carries a broader lesson about genotype-phenotype architecture. Genitourinary anomalies have been reported in approximately 15 to 35 percent of individuals with 17p11.2 deletions, including collecting-system duplication, renal agenesis or ectopia, and ureterovesical obstruction, yet they are essentially absent from comparable cohorts of patients with intragenic RAI1 point variants. A 2006 genotype-phenotype study of 31 patients found renal or urinary abnormalities in 15 percent of deletion carriers and in none of the 11 individuals carrying RAI1 mutations. The implication is that genes elsewhere in the deleted interval, not RAI1 alone, shape the structural anomalies, meaning Smith-Magenis syndrome caused by a large deletion is best understood as a contiguous-gene disorder with a wider clinical footprint. The closest prior comparator in the literature was an eight-year-old boy with bilateral grade IV reflux who ultimately required ureteroplasty on both sides; the present case extends that picture into infancy with quantitative renal scintigraphy.

Management proceeded along multiple tracks simultaneously. The acute infection responded to cefoperazone/sulbactam, followed by oral amoxicillin/clavulanate, and continuous antibiotic prophylaxis at 76 milligrams once daily at bedtime was initiated, a strategy supported by randomized trial evidence for infants with grade III to V reflux, including the 2014 RIVUR trial and a 2023 European study in infants. Levothyroxine was resumed, and thyroid function returned to normal. A planned phimosis surgery had to be postponed after the boy suffered an afebrile seizure during sleep, which was treated with oxygen, monitoring, and phenobarbital; video-electroencephalography later showed no definite abnormality. Mouse models have shown that loss of Rai1 enhances hippocampal excitability and epileptogenesis, providing biological context for seizure susceptibility, but the authors decline to diagnose epilepsy, instead describing brief ocular convergence episodes observed during follow-up as possible seizure-like events under continued evaluation.

By late August 2025, the trajectory was cautiously encouraging. Creatinine had fallen to 25.0 micromoles per liter, cystatin C to 1.39 milligrams per liter, and the estimated glomerular filtration rate stood at 103.66 milliliters per minute per 1.73 square meters, with a urine protein-to-creatinine ratio of 0.12 grams per gram and no recurrent infections. Thyroid indices normalized, and growth in height and weight was satisfactory, though gross-motor, fine-motor, and language delays persisted, with a Gesell developmental quotient of 72 recorded at 9.2 months. The case’s principal message extends beyond one child: when an infant presents with developmental delay and hypotonia alongside dysmorphic features, skeletal findings, genitourinary anomalies, and endocrine dysfunction, clinicians should think syndromically and order genomic testing capable of detecting copy-number variants, because microdeletions can slip past both routine karyotyping and exome workflows restricted to single-nucleotide changes. Catching Smith-Magenis syndrome early does not change the deletion, but it transforms care, replacing episodic firefighting with coordinated renal protection, thyroid replacement, neurologic surveillance, developmental rehabilitation, and informed genetic counseling for the family.

Subject of Research: Early infantile presentation of Smith-Magenis syndrome with bilateral high-grade vesicoureteral reflux, hypothyroidism, and seizure

Article Title: Case Report: Smith-Magenis syndrome with bilateral high-grade vesicoureteral reflux, hypothyroidism, and seizure in infancy

Article References: Cheng, Y., Liu, X., Yang, L., & Xu, J. (2026). Case Report: Smith-Magenis syndrome with bilateral high-grade vesicoureteral reflux, hypothyroidism, and seizure in infancy. Frontiers in Pediatrics, 14, Article 1906694. https://doi.org/10.3389/fped.2026.1906694

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1906694

Keywords: Smith-Magenis syndrome, RAI1, 17p11.2 deletion, vesicoureteral reflux, congenital hypothyroidism, DUOX2, whole-exome sequencing, copy-number variant, pediatric nephrology, seizure, developmental delay, case report

The condition in question is 19p13.3 microdeletion syndrome, a rare and clinically heterogeneous genomic disorder caused by the loss of a small stretch of genetic material near the tip of the short arm of chromosome 19. Because the deleted segment can vary considerably in size from one patient to another, the syndrome does not present as a single recognizable disease. Instead, affected individuals may show global developmental delay, a range of congenital anomalies, and distinct craniofacial differences, with the precise combination and severity of symptoms depending heavily on which genes fall within the deleted region. This genotype-phenotype relationship is a central theme in the literature on the disorder and is precisely what makes each new case report valuable to clinicians trying to map the syndrome’s boundaries.

In the newly reported case, the infant was referred for evaluation of multisystemic complications that had already produced a daunting list of problems. Clinical examination revealed congenital heart defects and severe cardiomegaly, an abnormal enlargement of the heart that in this instance proved fatal. The child also presented with limb anomalies, macrocephaly, or an unusually large head, and recurrent pulmonary infections that compounded the clinical picture. Gastrointestinal manifestations, including vomiting and diarrhea, were a prominent feature of the illness. The authors note that digestive symptoms have rarely been reported in association with this condition, making their patient’s presentation particularly noteworthy for the expanding clinical record.

The diagnostic breakthrough came through a technique known as oligo-array comparative genomic hybridization, or oligo-array CGH. This laboratory method works by comparing a patient’s DNA against a reference genome on a microarray chip populated with thousands of short oligonucleotide probes covering the genome. Differences in fluorescence signal reveal regions where the patient has either lost or gained genetic material, often at a resolution far finer than a standard karyotype can achieve. In this case, the analysis uncovered a deletion measuring 1.8 megabases, a stretch of DNA encompassing 55 genes. Identifying the exact size and gene content of such a deletion is essential, because it allows clinicians to compare the patient against previously reported cases and to begin assigning specific features to specific genes.

Among the 55 genes within the deleted interval, several have already attracted attention in earlier studies of 19p13.3 deletions. The MAP2K2 gene, which encodes the kinase MEK2, a component of the RAS-MAPK signaling pathway that governs cell proliferation and differentiation, has been implicated in cases resembling cardiofaciocutaneous syndrome, a RASopathy characterized by heart defects, distinctive facial features, skin abnormalities, and developmental delay. Previous work has also suggested that PIAS4, a gene involved in sumoylation and the regulation of protein function, may be a major contributor to the proximal 19p13.3 microdeletion phenotype. Other genes in the region have been linked to cardiac development, including members of the ZBTB family of transcription factors, and to brain growth, such as the lamin genes whose variants cause primary microcephaly and the cell-cycle regulator CDH1, whose disruption has been associated with microcephaly, psychomotor retardation, and epilepsy.

The gastrointestinal findings in this case deserve particular emphasis. Although congenital heart disease and neurodevelopmental problems dominate the published literature on 19p13.3 microdeletions, digestive complications have appeared only sporadically. One earlier report described a newborn with a 19p13.3 deletion including MAP2K2 who had cardio-facio-cutaneous syndrome together with gastrointestinal defects, and another described a child with a chromosome 19p13.3 deletion in the context of Peutz-Jeghers syndrome and congenital heart defect. The vomiting and diarrhea observed in the Iranian infant, occurring alongside severe cardiac disease, suggest that the digestive system may be more frequently involved in this syndrome than the sparse literature indicates, and that the gene content of larger deletions may include factors necessary for normal gastrointestinal development or function.

The fatal outcome of the case also highlights the severity that 19p13.3 microdeletions can reach when the deleted segment is large. Severe cardiomegaly in an infant is a grave finding, often reflecting structural heart defects, myocardial dysfunction, or volume overload, and in combination with recurrent pulmonary infections it can create a lethal cycle in which cardiac compromise worsens respiratory disease and vice versa. The authors describe their patient’s phenotype as complex and multisystemic, and the report’s title explicitly characterizes the case as fatal. For clinicians, the message is that infants presenting with combinations of congenital heart defects, unusual head size, limb anomalies, and unexplained gastrointestinal symptoms may warrant genomic investigation even when the initial suspicion does not point to a chromosomal disorder.

The technique used to reach the diagnosis also carries a broader lesson for pediatric medicine. Oligo-array CGH has become a cornerstone of modern cytogenetics precisely because it can detect copy-number variants, deletions, and duplications that are invisible under the microscope. In rare syndromes such as this one, where the phenotype overlaps with many other conditions, genomic analysis is often the only route to a definitive answer. The authors of the report argue that their case underscores the importance of such analysis in understanding the underlying disease mechanisms of the syndrome. Each precisely characterized deletion narrows the search for the genes responsible for individual features, a process already illustrated in the literature by a case that narrowed the subtelomeric 19p13.3 microdeletion region to just 46 kilobases in a patient with cardiac, skeletal, speech, and motor traits.

The accumulated case reports on 19p13.3 deletions now paint a picture of remarkable phenotypic diversity. Published accounts include children with ocular manifestations, ptosis leading to the diagnosis of MAP2K2-linked cardiofaciocutaneous syndrome, lambdoid synostosis in combination with an inherited 16p13.11 microduplication, polyotia, high myopia, learning difficulties, and, in the mirror-image condition of 19p13.3 microduplication, nephrotic syndrome. Recent reports have expanded the spectrum further, describing feeding dysfunction and neurodevelopmental involvement in MAP2K2-related cardiofaciocutaneous syndrome type 4, and retinal development roles for genes such as RAX2. Against this backdrop, the new Iranian case, with its severe cardiomegaly and gastrointestinal manifestations, extends the known boundaries of the syndrome once again and reinforces the principle that deletion size and gene content are the primary determinants of clinical severity.

The research team, led by clinicians at Ali Asghar Children’s Hospital and Iran University of Medical Sciences in Tehran, obtained written informed consent from the parents and received ethics approval from their institution’s ethics committee. The authors declare no competing interests and no external funding for the work. While a single case cannot resolve which of the 55 deleted genes drives which symptom, reports of this kind serve as the raw material for that long-term effort, allowing researchers worldwide to align clinical features with genomic coordinates. For families affected by rare chromosomal disorders, and for the physicians who care for them, each carefully documented case shortens the diagnostic odyssey for the next child and brings the field a step closer to understanding how the loss of a tiny fragment of chromosome 19 can ripple through the development of the heart, the brain, the limbs, and the gut.

Subject of Research: 19p13.3 microdeletion syndrome and its clinical phenotype in a fatal infant case

Article Title: Phenotypic spectrum of 19p13.3 microdeletion: a fatal infant case with severe cardiomegaly and gastrointestinal manifestations

Article References: Eshghi, A., fargi, M. A., Pandi, M., & Tasharrofi, B. (2026). Phenotypic spectrum of 19p13.3 microdeletion: a fatal infant case with severe cardiomegaly and gastrointestinal manifestations. Molecular Biology Reports, 53(1), Article 1633. https://doi.org/10.1007/s11033-026-12791-x

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12791-x

Keywords: 19p13.3 microdeletion, chromosome 19, cardiomegaly, congenital heart defects, gastrointestinal manifestations, oligo-array CGH, MAP2K2, rare genetic disorder, developmental delay, recurrent pulmonary infections, copy-number variant, clinical genetics