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. Author manuscript; available in PMC: 2026 Jun 21.
Published in final edited form as: Am J Med Genet A. 2025 Aug 21;200(1):205–214. doi: 10.1002/ajmg.a.64233

Case series of Nizon-Isidor Syndrome by heterozygous variants in MED12L with further evidence of mitotic instability in one case with diploid-triploid mosaicism

Russell Stewart 1,#, Kimberly M Ezell 2,#,†, Deanna S Bell 3, Brian Corner 2, Ashley McMinn 2, Joy D Cogan 2, Rizwan Hamid 2, Lynette Rives 2, John A Phillips III 2, Nina Paddu 4, Gitanjali Srivastava 5, Ronit Marom 6,7, Farah A Ladha 6,7, Claudia Soler-Alfonso 6,7, Rachel Franciskovich 6,7, Mary Koziura 2, Sumit Pruthi 8, Gabriele Richard 9, Christina B Sheedy 9; Undiagnosed Diseases Network, Thomas Cassini 2
PMCID: PMC13282996  NIHMSID: NIHMS2174757  PMID: 40838347

Abstract

Nizon-Isidor Syndrome is a rare disorder caused by heterozygous variants in MED12L, with only 8 documented cases in the literature. Here we present three additional cases of this syndrome. Proband 1 was a seven-year-old female who presented with developmental delay, right-leg hemihypertrophy, laryngeal cleft, esotropia, abnormal skin pigmentation, sectoral iris hypopigmentation, dysphagia, periventricular nodular heterotopia, seizures, morbid obesity, and a pelvic kidney. Genome sequencing revealed a MED12L variant, NM_053002.5:c.3559+2T>G. Both computational models and transcriptomic analysis confirmed that this variant induced splice loss of MED12L exon 25. Probands 2 and 3 presented with overlapping phenotypes of developmental delay; sequencing confirmed c.3441_3444dup; p.(G1149Nfs*13) and seq[GRCh37] del(3)(q25.1q25.1) chr3:g.?_151075120 variants affecting MED12L. Further investigation found diploid-triploid mosaicism in Proband 1, supporting the hypothesis that loss of MED12L function may increase risk for other cytogenetic abnormalities. Probands 2 and 3 did not harbor evidence of additional cytogenetic aberrations. In Proband 1, caloric restriction and semaglutide–pramlintide combination therapy was started at age eight and was effective in weight reduction. Overall, this report expands the phenotypic spectrum of Nizon-Isidor Syndrome, highlights a potential link between MED12L and cytogenic abnormalities, and demonstrates a case of weight loss through GLP-1 therapy in a child with a genetic obesity syndrome.

Keywords: Nizon-Isidor Syndrome, MED12L, Mediator complex, diploid-triploid mosaicism, mitotic instability, semaglutide

Introduction

Mediator complex subunit 12-like (MED12L) is a paralog of MED12, a core component of the Mediator Complex, a large multiprotein assembly responsible for relaying regulatory signals from DNA-bound proteins to the basal transcription machinery near the transcription initiation site. It has been shown that MED12L can substitute for MED12 within this complex1, highlighting its importance in transcriptional regulation. Given the Mediator Complex’ central role in eukaryotic transcription, germline variants in its cyclin-dependent kinase subunits (CDK-Mediator components) have been associated with a variety of neurodevelopmental, psychiatric, and cardiac disorders2.

Nizon et al3. characterized the phenotype associated with heterozygous, loss-of-function variants in MED12L, referred to as Nizon-Isidor Syndrome (OMIM #618872)2. Phenotypes consistently shared amongst the seven individuals included in the report included behavioral disturbances, developmental delay, and hypoplasia or agenesis of the corpus callosum. A spectrum of phenotypic variability was also observed within this syndrome, including dysmorphic features (high nasal root, narrow and arched palate, and hand anomalies), hypotonia, and chronic constipation. Additionally, 2 of the 7 subjects described in this article carried additional copy number and structural variants beyond MED12L without evidence of parental inheritance: One patient harbored a 10q11.21 duplication and another harbored both a 4q34.3 duplication and a t(9;18)(p13;q12.2) balanced translocation. (A separate 22q11.2 duplication in the series was shown to be maternally inherited, and a 2p16.3 deletion of NRXN1 overlapped with a common deletion observed in the Database of Genomic Variants, also suggesting inheritance).

In a correspondence, Ferraz et al.4 reported another subject with a pathogenic MED12L single nucleotide variant and two additional balanced reciprocal translocations. Given this further datum of copy number and structural variants in Nizon-Isidor syndrome, the Ferraz group hypothesized that patients with MED12L variants may have an increased propensity for chromosomal instability.

Here, we expand the field’s corpus of Nizon-Isidor syndrome with three additional patients who were diagnosed following evaluations at the Undiagnosed Disease Network (UDN) at Vanderbilt University Medical Center5 (VUMC) and Baylor College of Medicine (BCM). In addition, one further unrecognized case of Nizon-Isidor syndrome was identified in our literature review. Together, these new cases refine our understanding of this disorder’s phenotype and provide further evidence for the MED12L-cytogenic abnormality hypothesis.

Methods

Proband 1 received written informed consent and IRB approval through VUMC. Probands 2 and 3 received written informed consent through BCM/Texas Children’s Hospital (TCH). Clinical and molecular diagnostic workups were performed by the VUMC UDN (Proband 1) and the BCM Department of Molecular and Human Genetics (Probands 2, 3).

Initial autism spectrum disorder (ASD) and primary immunodeficiency gene sequencing panels were outsourced to Prevention Genetics6 and Invitae7, respectively. Subsequent karyotype analyses and chromosomal microarray (CMA) were performed for proband 1 by Baylor Genetics. Proband 1 received genome sequencing (GS) on fragmented and pooled genomic DNA through Baylor Genetics. Exome sequencing (ES) was performed by GeneDx for probands 2 and 3.

During cDNA sequencing, a lymphoblastoid cell line from the proband was incubated with and without puromycin (100ug/ml) overnight before harvesting. Cells were harvested for total RNA using the RNAeasy Mini Kit (Qiagen). Total RNA (3 μg) was reverse transcribed into cDNA with the SuperScript III First-Strand Synthesis System and oligo dT (Invitrogen). PCR was performed on cDNA using Platinum SuperFi PCR Master Mix (Invitrogen). Primers 5’-AAGCAGAAATTGAGGCAGAGAGA-3’ and 5’-ATGCTTTTCCCACAGGATTTTGG-3’ were annealed at 58°C to amplify the exonic region spanning the splice site variant (c.3559+2) of MED12L. Reverse transcriptase PCR products were then sequenced using an internal primer 5’-ACGTGTGGGGGTTTAATGATGTA-3’.

Clinical Synopsis

Proband 1: Clinical Features and Nizon-Isidor Syndrome Diagnosis

Proband 1 is 7-year-old female with a prior extensive negative workup who presented to the UDN at VUMC. She was born at 38 weeks via emergency cesarean delivery for nonreassuring fetal heart tones, following a pregnancy complicated by maternal smoking, preeclampsia, and intrauterine growth restriction. In the immediate postnatal period, she exhibited temperature instability, hyperbilirubinemia, and poor feeding. She later demonstrated global developmental delay. She began walking at 18 months; by 8 years of age, she could climb stairs without alternating feet and speak in simple sentences. She showed rapid weight gain beginning at 6–7 months of age, with BMI z-scores of +6.5 by 30 months and +8.7 by 6.5 years.

At her initial medical genetics evaluation (age 2 years), she exhibited right hemihypertrophy from the face to the lower extremity, particularly evident in leg length discrepancy. She also showed macrocephaly (head circumference at the 97th percentile) and weight above the 99th percentile (z=4.26), with height at the 56th percentile (z=0.16). Dysmorphic features included a short philtrum, deep-set eyes, a bulbous nasal tip, tapered fingers, and borderline hypoplastic thumbs. She lacked overt ear or palate anomalies, though a laryngeal cleft was found. Patchy, irregular hyperpigmented streaks and whorls were evident over her skin. (Figure 1). Ophthalmologic evaluation showed sectoral iris hypopigmentation and esotropia, and neurologic examination noted diffuse hypotonia.

Figure 1. Clinical Photographs of Proband 1.

Figure 1.

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A. Progressively worsening obesity was evident between ages 2 weeks, 2 years, and 6 years. Leg length discrepancy is visible at age 2 years. B. Hyperpigmented macules suggestive of Hypomelanosis of Ito.

Brain magnetic resonance imaging (MRI) at age 2 years identified a large nodular subependymal heterotopia in the occipital horn of the right lateral ventricle. Ill-defined T2/FLAIR hyperintensity in the subjacent white matter suggested a possible associated cortical dysplasia. Cortical thickening versus an area of dysgyria involving the frontal cortex was also noted (Figure 2). A repeat MRI at age 4 years redemonstrated similar findings with an additional finding of mild sulcal and ventricular prominence.

Figure 2. Diagnostic Testing of Proband 1.

Figure 2.

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A: Brain MRI. Subependymal heterotopia (arrow) is noted in the right lateral ventricle. B: MED12L (NM_053002.5) cDNA sequencing. Top: Heterozygous peaks in the proband’s cDNA suggest exon 25 is skipped on one allele, consequent from the c.3559+2T>G variant. Bottom: Reference sequence control.

Proband 1’s clinical course was significant for the onset of focal seizures managed with levetiracetam at 2 years. She developed severe disseminated HSV-1 at 5 years of age with subsequent normal natural killer cell function, CD107a flow cytometry, and vaccine responses (diagnostic studies which would typically imply normal innate cytotoxic cell function, normal degranulation of cytotoxic cells8, and the ability to mount successful B- and T-cell mediated adaptive immune responses, respectively). She was placed on valacyclovir prophylaxis for 3 years with prompt cutaneous recurrence after this medication was discontinued. She subsequently developed a chronic leukocytosis with a normal bone marrow biopsy (and a 46,XX karyotype observed in bone marrow cells). At age 5 years, an abdominal ultrasound also incidentally detected a right pelvic kidney. Subsequent pulmonary history was marked by impaired airway clearance and recurrent pneumonias. Obesity-related comorbidities included metabolic dysfunction-associated steatotic liver disease, type II diabetes, hypertension, severe obstructive sleep apnea, and obesity-related hypoventilation.

The proband’s mother has a history of attention deficit hyperactivity disorder (ADHD) managed with cognitive behavioral therapy and medication. There is little known about her father’s health history. She has a half maternal sister, half maternal brother, half paternal sister, and half paternal brother, none of whom are affected. The proband’s mother’s identified ethnicity is white, and her father’s identified ethnicity is African American. There are no other similarly affected individuals in the family.

CMA on peripheral blood found no abnormalities (arr(1-22,X)x2). Methylation analysis for Prader-Willi syndrome, recommended due to her obesity, was negative. A Prevention Genetics ASD and intellectual delay gene sequencing panel6 identified variants of uncertain significance in PDE11A, inherited maternally, and in POGZ, not inherited maternally. PDE11A did not explain Proband 1’s phenotype, as her Cushing’s disease workup was negative. Heterozygous variants in POGZ are more commonly associated with microcephaly (not macrocephaly, as in Proband 1), broad nasal roots with flat bridges (not bulbous nasal tips), and hearing loss9 (also not seen in this proband). As such, this POGZ variant of uncertain significance was also not thought to explain Proband 1’s phenotype. A subsequent Invitae primary immunodeficiency panel7 ordered by immunology to identify the underlying etiology of the patient’s leukocytosis and recurrent disseminated HSV-1 infections yielded only heterozygous variants in genes associated with conditions that follow autosomal recessive inheritance patterns (Supplement A). Metabolic testing produced no relevant findings.

A comprehensive genetic evaluation was performed in the UDN program. Given her pattern of hyperpigmented patches, mosaicism was considered. GS was completed on three tissue types (blood, hypopigmented skin, and hyperpigmented skin) through Baylor Genetics. All samples yielded a heterozygous MED12L variant, NM_053002.5:c.3559+2T>G, subsequently confirmed by Sanger sequencing. The variant was not identified in her mother’s blood sample; the proband’s father was not available for testing. Informatic analysis of this variant found that it had a SpliceAI score of 1.0, suggesting a loss of exon 25. RT-PCR based cDNA analysis from lymphoblasts confirmed the absence of exon 25, an in-frame exon, in the spliced transcript (Figure 2). This exon is absent from multiple transcripts, however none are the MANE select transcript (ENST00000687756, NM_001393769.1). There are no MANE plus transcripts denoted for this gene. A review of the expression profile in GTEx data shows that of the tissues with any appreciable expression of MED12L, only the tibial nerve has any significant expression of a transcript lacking exon 25 (ENST00000480026.1).

At the time of initial diagnosis, Proband 1’s variant was not previously reported in gnomAD, Nizon et al., or other reports. Subsequently, an entry of one female of African ancestry with this variant was uploaded to gnomAD (allele frequency: 0.00001%). An AlphaFold protein structure, but no experimental protein structures, were available for human MED12L. An alignment of the amino acid sequence encoded by Proband 1’s variant is aligned to the reference MED12L protein sequence in (Supplement C). AlphaFold demonstrated variable model confidence in the secondary and tertiary structures of the region of the MED12L protein encoded by exon 25. It suggested the region encodes core alpha helices connected by linker regions. No known domains or post-translational modifications were recorded for this protein sequence in UniProt. However, exon 25’s protein sequence homolog in the better-characterized MED12 contains a lysine residue known to be a SUMOylation site10; the codon encoding this lysine is conserved in MED12L. Overall, the inconclusive extant structural data for exon 25 of MED12L was not sufficient to alone label Proband 1’s variant as pathogenic. This variant was thus classified as likely pathogenic, as initially determined by Baylor Genetics. The proband’s clinical features (deep-set eyes, bulbous nasal tip, global developmental delay, and seizures) provided further clinical support for a diagnosis of Nizon-Isidor Syndrome.

Proband 2: Clinical and Molecular Features

Proband 2 is a 5-year-old male with developmental delay, ASD, behavioral problems, ADHD and sleep disorder. Pregnancy was complicated by late presentation to prenatal care and prenatal exposure to substances of abuse (marijuana and tobacco use). The mother was 21 years old and the father was 49 years old at conception. The proband was born at term (39 weeks gestational age) via induced vaginal delivery due to maternal pre-eclampsia. Birth weight was 6 lb 10 oz and birth length was 18.5 inches (appropriate for gestational age). Meconium tests were negative for illicit drugs. He was placed with his adoptive family on day of life 1.

Regarding his development, he met early gross motor milestones (crawled and sat up at 5-6 months, walked at 9 months) but had incoordination and delayed visual-motor skills. He had speech impairment and was diagnosed with severe articulation-phonological disorder. Neuropsychiatric and neurological evaluations at age 4 years were consistent with age-appropriate cognitive function, but he met criteria for a diagnosis of ASD and ADHD. Excessive weight gain was first noted during early childhood (around age 3 years).

The proband currently has obesity (BMI 27 kg/m2, >99 %ile). He is followed by endocrinology for premature adrenarche and has advanced bone age. His medical history is otherwise significant for sleep disturbance (obstructive sleep apnea and frequent night awakenings), astigmatism, allergic rhinitis, asthma and recurrent ear infections (requiring adenotonsillectomy and repeat myringotomy with ear tube placement). The proband’s identified ethnicity is African American, and family history is unknown due to adoption status.

On physical examination, no dysmorphic craniofacial features were noted. The patient had two normal brain MRI and a normal electroencephalogram (EEG). Audiology exam showed normal hearing. Genito-renal ultrasound showed no abnormalities. Initial genetic testing included a CMA and Fragile X test, which were normal. ES through GeneDx then revealed a mosaic, heterozygous pathogenic variant, c.3441_3444dup, p.(G1149Nfs*13) in MED12L (Supplement E). In saliva, this variant was present in approximately 11% of 47 sequencing reads.

Proband 3: Clinical and Molecular Features

Proband 3 is a 13-year-old male with developmental delay, learning difficulties, ADHD, and motor tics. Pregnancy was uncomplicated. The mother was 21 years old, and the father was 22 years old at conception. He was born at term (39 weeks gestational age) via spontaneous vaginal delivery. Birth weight was 6 lb 7 oz (appropriate for gestational age).

He had global developmental delay. He walked at 18 months old and said his first word at 3 years old. He began speaking after initiation of speech therapy at 4 years old. He was diagnosed with ADHD at 6 years old and had a neuropsychiatric evaluation at 7 years old, which demonstrated cognitive function below age-appropriate norms and met criteria for ADHD.

His medical history was otherwise significant for motor tics and asthma. His identified ethnicity was white and family history was significant for a paternal half-brother with non-verbal autism spectrum disorder and father with learning difficulties. (His father, however, successfully graduated high school.)

At the time of medical genetics evaluation, he met the 11th percentile for height (which was appropriate to his mid-parental height), the 13th percentile for weight, and the 22nd percentile for head circumference. On physical examination, no dysmorphic craniofacial features were noted. The patient had never received brain imaging. Audiology exam showed normal hearing. Initial workup included normal CMA and Fragile X testing. Duo ES through GeneDx then revealed a heterozygous partial gene deletion of at least 9 kb within 3q25.1 (seq[GRCh37] del(3)(q25.1q25.1) in MED12L (Supplement F). The deletion was not inherited from the tested mother. A heterozygous, likely pathogenic variant in TRMT1 (c.1168C>T p.R390*) was also identified. However, a second variant was not identified, thus excluding TRMT1’s resultant autosomal recessive intellectual developmental disorder11.

The clinical and genetic features of Probands 1, 2, and 3 are tabulated in (Supplement B). The supplement includes a comparison with all other published cases of Nizon-Isidor Syndrome identified during a literature review: the original Nizon case series3, the Ferraz research letter4, and one previously-unrecognized proband from a translational case series on pediatric epilepsy10.

Proband 1: Diploid-Triploid Mosaicism Diagnosis

Proband 1’s hemihypertrophy, leg length discrepancy, patchy skin pigmentary abnormalities, and obesity with related complications extended beyond a phenotype known to be associated with Nizon-Isidor Syndrome alone. Given the previously suggested cytogenic abnormalities stemming from heterozygous loss-of-function variants in MED12L, we performed karyotyping and a CMA on affected and unaffected skin biopsy specimens to explore the unexplained phenotype. Although CMA yielded normal results for each sample, karyotyping revealed diploid-triploid mosaicism in the normal skin (69,XXX[6]/46,XX[14]) and the hyperpigmented skin (69,XXX[10]/46,XX[10]). An earlier bone marrow karyotype obtained during an immunodeficiency workup did not suggest mosaicism in marrow tissue, in particular.

Proband 1: Management of Obesity

During Proband 1’s diagnostic odyssey, she was admitted to the VUMC pediatric intensive care unit for acute hypoxic and hypercarbic respiratory failure secondary to obesity at age 8 years. Caloric restriction to 1200 kcal/d was not successful in sustaining weight loss. Therefore, the Vanderbilt Medical Weight Loss Center was engaged to direct obesity-related medication management. Pre-admission medications including insulin glargine 38 u nightly, gabapentin 100 mg thrice daily, and levetiracetam 5 mL twice daily were noted to possibly contribute to the patient’s obesity. A diet centered around ultra-processed carbohydrates, a dearth of physical exercise due to musculoskeletal constraint, food preoccupation, and hyperphagia were also noted.

Known monogenic causes of obesity, including Prader-Willi Syndrome, were excluded given the proband’s extant methylation and GS data. While the proband’s clinical features could be consistent with Bardet-Biedl syndrome, GS data did not identify a culprit variant. Setmelanotide was initiated for a presumed clinical diagnosis of Bardet-Biedl Syndrome but was discontinued due to a paradoxical reaction of worsening hyperphagia and accelerating weight gain.

Semaglutide 0.25 mg weekly was started off-label. Though clinical trial evidence available at the time of treatment only demonstrated the efficacy of GLP-1 therapy for weight loss in adolescents as young as 12 years of age13, the risk to life of the proband’s obesity outweighed the risks of limited evidence for GLP-1 agonists in her age cohort. Preprandial pramlintide was also initiated at 15 μg and escalated to 30 μg. Beyond weight loss, this regimen improved glycemic control and enabled the proband to discontinue synthetic insulin. Side effects included mild constipation successfully treated with polyethylene glycol. Over a two-month inpatient admission with 1200 kcal/day caloric restriction and physical therapy, the proband’s BMI decreased from 56.7 to 47. Her food preoccupation and hyperphagia also decreased.

Discussion

The Mediator Complex: Translational Science Considerations in Nizon-Isidor Syndrome

The clinical phenotype of Nizon-Isidor Syndrome as seen in this case series is caused by alterations in the function of the MED12L protein. An expanding corpus of basic and translational science research is elucidating how variants in MED12L induce multifaceted changes to the cell cycle.

MED12L is a kinase which coordinates with Mediator to form the CDK-Mediator complex. In response to transcription factor binding, CDK-Mediator assembles the preinitiation complex (PIC). The PIC controls RNA polymerase II’s enhancer-dependent transcription1. In addition to this role in regulating expression of protein-coding genes and some functional RNAs, CDK-Mediator regulates chromosome architecture14. Enhancers may be megabases remote from the promoters they target. Transcription activation requires spatial approximation of these distant sequences. CDK-Mediator accomplishes this by condensing “transcription hubs” of intrinsically-disordered protein complexes to loop chromatin into favorable topologies1. Ascending a level beyond chromatin topology, Mediator also regulates proper centromere function. During genome replication, Mediator localizes to the centromere, triggering RNA polymerase II-mediated transcription of the noncoding RNAs requisite for proper kinetochore formation during cell division15.

The field of cancer biology has provided further insight into the pathomechanisms of MED12L variants and mitotic instability. Studies of human tumor pathology samples have shown that MED12L variants causing either gain or loss of function can drive tumorigenesis. Documented consequences of such mutations include colorectal cancer (through epigenetic inactivation or missense mutations including p.V1694L and p.V2042M)16, prostate cancer (through amplification via hypomethylation or duplication)17, and uterine leiomyomata (by gain-of-function missense variants, most often c.131G>A, but not by knockout)18. Rodent and immortalized cell culture studies of uterine leiomyomata have served as a model system for this oncogenic process. The uteri of mice knocked-in with heterozygous MED12L variants chosen from human tumor sequences demonstrate high rates of chromosomal aberrations, including deletions and duplications that may be dozens to thousands of kilobases in length.19. Evidence from immortalized human cell culture suggests that this instability may stem from aberrant R loop-induced replication stress during DNA replication20. While other Mediator variants cause known cancer syndromes2, the patients in this case series and in previous reports of Nizon-Isidor Syndrome3,4,12 have not yet shown evidence of elevated neoplasia risk.

Given this known role of CDK-Mediator in regulating stable mitosis, Ferraz et al proposed that heterozygous loss of function variants in MED12L may predispose patients with Nizon-Isidor Syndrome to chromosomal instability, as evident in their new case of a pathogenic MED12L variant with two concomitant balanced reciprocal translocations. This hypothesis would explain the frequency of additional chromosome structural abnormalities identified in Nizon et al’s initial description of this disease4.

Probands 1, 2, and 3: Refining and Expanding the Nizon-Isidor Syndrome Phenotype

Our study’s probands presented with shared neurodevelopmental, gastrointestinal, and immune dysfunction symptoms evident by both clinical presentation and genotype as two further reference cases of Nizon-Isidor Syndrome. These reinforce and refine the syndrome’s phenotype as described by Nizon and Ferraz. A comparison of our three probands’ phenotypic similarities and differences to all other known cases of Nizon-Isidor Syndrome is included in (Supplement B). Proband 1, however, presented with a broader constellation of findings. After further workup, this presentation was attributed to a dual diagnosis of Nizon-Isidor Syndrome and diploid-triploid mosaicism. Some of Proband 1’s clinical findings are more consistent with prior descriptions of Nizon-Isidor Syndrome. Her dysmorphology, including deep-set eyes and bulbous nasal tip, were recapitulated in the Mínguez-Viñas proband and three of the Nizon probands. Other medical complications, specifically chronic constipation and GERD, were seen in Proband 3 in our case series and in four of the Nizon probands. Cortical white matter abnormalities on brain MRI were also seen in our proband, three Nizon cases, and the Ferraz case. In contrast, some of Proband 1’s other phenotypic features, including hemihypertrophy, childhood-onset obesity, Hypomelanosis of Ito, and hypotonia, are highly consistent with diploid-triploid mosaicism21,22. Some features, notably intellectual delay and pediatric epilepsy, may be caused by either disorder.

Diploid-triploid mosaicism is a cytogenetically distinct process: In diploid-triploid mosaicism, individuals have a karyotype in which some (diploid) cells have the usual 46 chromosomes and other (triploid) cells have an additional haploid set of chromosomes, for a total of 69.23 This extra set of chromosomes is caused by incomplete chromosomal segregation and cell division, either of the polar body during oogenesis or of spermatocytes during spermatogenesis.24 Following fertilization with one haploid and one diploid gamete, a new embryo undergoes heterogenic mitosis, forming an admixture of diploid and triploid cells, the ultimate tissue destinations of which are unpredictable and dependent upon their comparative locations within the blastocyst.25 In many embryos (up to 50% in some in vitro studies), DNA repair mechanisms enable an embryo to self-correct from a triploid to a diploid karyotype before further development.24,26

Even given this distinct molecular mechanism, Mediator’s known roles in both chromatin regulation and in kinetochore formation suggest that aberrancies in complex function could induce either change — copy number variants or variation in ploidy. Proband 1’s expanded phenotype suggests that secondary mitotic errors, including diploid-triploid mosaicism not previously described in Nizon-Isidor Syndrome cases, may occur more frequently in this condition and possibly explain some of this disease’s high phenotypic variability.

A Literature Review: Cytogenic Abnormalities in Similar Mediatoropathies

To further investigate the potential hypothesis that disruptions to Mediator complex function copresent with cytogenic abnormalities, we conducted a literature review of congenital neurodevelopmental disorders of other proteins in the CDK-Mediator complex (CDK8, CDK19, MED12, MED13, and MED13L). We identified 58 patient cases of such congenital mediator disorders in which authors reported results from structural genetic studies (karyotype, chromosomal microarray, comparative genomic hybridization, fluorescent in-situ hybridization, or eXome-hidden Markov models). Of these 58 cases, 4 harbored additional de novo copy number variants27,28 and 3 harbored de novo structural variants (namely partial trisomy 17p29, a 47,XYY difference of sexual development30, and mosaicism27). Patients identified in this literature review are tabulated in (Supplement D). While these additional cases provide further evidence to this hypothesis, more comprehensive population-scale modeling of the incidence of structural variants and further basic science research into pathomechanisms underlying Mediator, mitosis, and chromosomal stability are needed to draw formal conclusions.

Clinical Pearl: GLP-1 Therapy and Genetic Obesity Syndromes

GLP-1 drugs, a class of therapeutics originally designed to treat type II diabetes mellitus by mimicking the endogenous glucagon-like peptide 1 (GLP-1) hormone’s insulin secretagogue activity, have recently gained widespread use in the treatment of obesity. These drugs are postulated to induce weight loss in humans by binding to GLP1R receptors in the brain and in peripheral vagal afferents, activating proopiomelanocortin (POMC)-releasing neurons in the hypothalamus to inhibit the release of orexants including neuropeptide Y (NPY) and Agouni-related peptide (AGRP). This anorexant effect reduces food intake, causing weight loss.31 Proband 1’s medical weight loss also demonstrates a case in which combination therapy with a GLP-1 receptor agonist and pramlintide promoted weight loss and improved glycemic control in a child with metabolic syndrome secondary to diploid-triploid mosaicism (an established genetic cause of obesity23). However, as GLP-1 agonist therapy was initiated in tandem with multimodal dietary, physical therapy, and medication reconciliation changes, it is difficult to query the efficacy of semaglutide therapy individually during Proband 1’s medical management. Following proband 1’s diagnostic odyssey, randomized trials like the SCALE Kids trial independently concluded with more substantial evidence that liraglutide is efficacious in the treatment of pediatric obesity32. Further research questions in this field remain open, like whether the efficacy of GLP-1 therapy differs in pediatric subpopulations with known genetic causes of obesity.

Conclusion

Like other Mediator complex disorders — and neurodevelopmental disorders, broadly — Nizon-Isidor Syndrome is a multisystemic, lifelong pathology. This report adds to the previously sparsely described phenotypic spectrum and supports the hypothesis that these patients are at risk for additional cytogenetic aberrations. Proband 1’s medical course also underscores the importance of medical weight loss therapy in children with genetic obesity syndromes and emphasizes the need for collaboration between clinical specialties, medical professions, and foundational scientists in knowledge generation, diagnosis, and clinical management of such conditions. Multidisciplinary clinical and research programs, such as the UDN, are helpful in navigating some of the barriers to diagnosis and further knowledge of rare diseases.

Supplementary Material

1

Acknowledgements

The authors are grateful to the patients and family for participating in the UDN. The authors are also grateful for the Baylor cases consenting to be a part of this report. This work was supported in part by the National Institutes of Health (NIH) Common Fund, NIH/NHGRI grant 15-HG-0130. Consortia: Collaborators of the Undiagnosed Disease Network (UDN) include Aaron Quinlan, Abdul Elkadri, Adeline Vanderver, Adriana Rebelo, Alan H. Beggs, Albert R. La Spada, Alden Huang, Alex Paul, Alexander Miller, Ali Al-Beshri, Alistair Ward, Allen Bale, Allyn McConkie-Rosell, Alyssa A. Tran, Andrea Gropman, Andres Vargas, Andrew B. Crouse, Andrew Stergachis, Anna Hurst, Anna Raper, Arjun Tarakad, Ashley Andrews, Ashley McMinn, Ashok Balasubramanyam, Barbara N. Pusey Swerdzewski, Beatriz Anguiano, Ben Afzali, Ben Solomon, Beth A. Martin, Bianca E. Russell, Brandon M Wilk, Breanna Mitchell, Brendan C. Lanpher, Brendan H. Lee, Brent L. Fogel, Brett Bordini, Brett H. Graham, Brian Corner, Brianna Tucker, Bruce Korf, Calum A. MacRae, Camilo Toro, Cara Skraban, Carlos A. Bacino, Carol Oladele, Caroline Hendry, Carson A. Smith, Cecilia Esteves, Changrui Xiao, Chloe M. Reuter, Christine M. Eng, Chun-Hung Chan, Colleen E. Wahl, Corrine K. Welt, Cynthia J. Tifft, Dana Kiley, Daniel J. Rader, Daniel Wegner, Danny Miller, Daryl A. Scott, Dave Viskochil, David A. Sweetser, David R. Adams, Deborah Barbouth, Deepak A. Rao, Devin Oglesbee, Devon Bonner, Donald Basel, Donna Novacic, Dustin Baldridge, Edward Behrens, Edwin K. Silverman, Elaine Seto, Elijah Kravets, Elisabeth Rosenthal, Elizabeth A Worthey, Elizabeth A. Burke, Elizabeth Blue, Elizabeth C. Chao, Elizabeth L. Fieg, Ellen F. Macnamara, Elsa Balton, Emily Glanton, Emily Shelkowitz, Emily Wang, Eric Allenspach, Eric Klee, Eric Vilain, Erin Conboy, Erin E. Baldwin, Erin McRoy, Esteban C. Dell’Angelica, Euan A. Ashley, F. Sessions Cole, Filippo Pinto e Vairo, Frances High, Francesco Vetrini, Francis Rossignol, Francisco Bustos, Fuki M. Hisama, Gabor Marth, Gail P. Jarvik, Gary D. Clark, George Carvalho, Gerard T. Berry, Ghayda Mirzaa, Giorgio Sirugo, Gonench Kilich, Guney Bademci, Hector Rodrigo Mendez, Heidi Wood, Herman Taylor, Holly K. Tabor, Hongzheng Dai, Hsiao-Tuan Chao, Hua Xu, Hugo J. Bellen, Hui Zhang, Ian Glass, Ian R. Lanza, Ingrid A. Holm, Isaac S. Kohane, Isum Ward, Ivan Chinn, J. Carl Pallais, Jacinda B. Sampson, James P. Orengo, James Verbsky, Jared Sninsky, Jason Hom, Jason Schend, Jennefer N. Kohler, Jennifer E. Posey, Jennifer Morgan, Jennifer Schymick, Jennifer Wambach, Jessica Douglas, Jiayu Fu, Jill A. Rosenfeld, Jimann Shin, Joan M. Stoler, Joanna M. Gonzalez, John A. Phillips III, John Carey, John E. Gorzynski, John J. Mulvihill, Joie Davis, Jonathan A. Bernstein, Jordan Whitlock, Jose Abdenur, Joseph Loscalzo, Joy D. Cogan, Julian A. Martínez-Agosto, Julie McCarrier, Justin Alvey, Kahlen Darr, Kaitlin Callaway, Kathleen A. Leppig, Kathleen Sullivan, Kathy Sisco, Kathyrn Singh, Katrina Dipple, Kayla M. Treat, Kelly Hassey, Kelly Schoch, Kevin S. Smith, Khurram Liaqat, Kim Worley, Kimberly Ezell, Kimberly LeBlanc, Kumarie Latchman, Lance H. Rodan, Laura Keehan, Laura Pace, Laurel A. Cobban, Lauren Blieden, Lauren C. Briere, Lauren Jeffries, Laurens Wiel, Layal F. Abi Farraj, Leoyklang Petcharet, LéShon Peart, Lili Mantcheva, Lilianna Solnica-Krezel, Lindsay C. Burrage, Lindsay Mulvihill, Lisa Schimmenti, Lisa T. Emrick, Lorenzo Botto, Lorraine Potocki, Lynette Rives, Lynne A. Wolfe, Maija-Rikka Steenari, Manish J. Butte, Margaret Delgado, María José Ortuño Romero, Maria T. Acosta, Marie Morimoto, Mariko Nakano-Okuno, Mark Gerstein, Mark Wener, Marla Sabaii, Martha Horike-Pyne, Martin G. Martin, Martin Rodriguez, Matt Velinder, Matthew Coggins, Matthew Might, Matthew T. Wheeler, MayChristine V. Malicdan, Megan Bell, Meghan C. Halley, Melissa Walker, Mia Levanto, Michael Bamshad, Michael F. Wangler, Michael Muriello, Michael Zimmermann, Michele Spencer-Manzon, Miranda Leitheiser, Mohamad Mikati, Mohamad Saifeddine, Monika Weisz Hubshman. Monkol Lek, Monte Westerfield, Mustafa Tekin, Nada Derar, Naghmeh Dorrani, Neil H. Parker, Neil Hanchard, Nicholas Borja, Nicola Longo, Nicole M. Walley, Nitsuh K. Dargie, Odelya Kaufman, Oguz Kanca, Orpa Jean-Marie, Page C. Goddard, Paolo Moretti, Patricia A. Ward, Patricia Dickson, Paul Berger, Paul G. Fisher, Pengfei Liu, Peter Byers, Pinar Bayrak-Toydemir, Precilla D’Souza, Queenie Tan, Rachel A. Ungar, Rachel Li, Rachel Mahoney, Ramakrishnan Rajagopalan, Raquel L. Alvarez, Rebecca C. Spillmann, Rebecca Ganetzky, Rebecca Overbury, Rebekah Barrick, Richard A. Lewis, Richard L. Maas, Rizwan Hamid, Rong Mao, Ronit Marom, Rosario I. Corona, Runjun Kumar, Russell Butterfield, Sanaz Attaripour, Sandesh Nagamani, Sara Emami, Seema R. Lalani, Serena Neumann, Seth Perlman, Shamika Ketkar, Shamil R. Sunyaev, Shilpa N. Kobren, Shinya Yamamoto, Shrikant Mane, Shruti Marwaha, Sirisak Chanprasert, Stanley F. Nelson, Stephan Zuchner, Stephanie Bivona, Stephanie M. Ware, Stephen B Montgomery, Stephen Pak, Steven Boyden, Suha Bachir, Surendra Dasari, Susan Korrick, Suzanne Sandmeyer, Tahseen Mozaffar, Tammi Skelton, Tanner D Jensen, Tarun KK Mamidi, Taylor Beagle, Taylor Maurer, Teodoro Jerves Serrano, Terra R. Coakley, Thomas Cassini, Thomas J. Nicholas, Timothy Schedl, Tiphanie P. Vogel, Vaidehi Jobanputra, Valerie V. Maduro, Vandana Shashi, Vasilis Vasiliou, Virginia Sybert, Vishnu Cuddapah, Wendy Introne, Wendy Raskind, Willa Thorson, William A. Gahl, William E. Byrd, William J. Craigen, Winston Halstead, Yan Huang, Yigit Karasozen, Yong-Hui Jiang

This work was funded in part through support from the Potocsnak Center for Undiagnosed and Rare Disorders

Funding

Received funding from the National Institute of Neurological Disorders and Stroke through Grant Number U01NS134349

Footnotes

Conflict of Interest Statement

Russell Stewart declares a potential conflict of interest relevant to this publication. Specifically, he was an employee of Singular Genomics, a genomics device manufacturer, from July 2020 until July 2022. He received and continues to hold company stock options from this employment. He has not received compensation from or performed work for this company since July 2022.

Gabriele Richard and Christina B. Sheedy are employees of and may own stock in GeneDx.

No other authors listed above report conflicts of interest relevant to this manuscript.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS2174757-supplement-1.pdf (1MB, pdf)

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