Phenotypic expansion of <i>KMT2D‐</i>related disorder: Beyond Kabuki syndrome

Baldridge, Dustin; Spillmann, Rebecca C.; Wegner, Daniel; Wambach, Jennifer A.; White, Frances V.; Sisco, Kathleen; Toler, Tomi L.; Dickson, Patricia I.; Cole, F. Sessions; Shashi, Vandana; Grange, Dorothy K.

doi:10.1002/ajmg.a.61518

Cited by 26 publications

(33 citation statements)

References 62 publications

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“…These patients' unique clinical features were most notable for choanal atresia, hypoplastic nipples, branchial apparatus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. One group also noted the presence of interstitial lung disease in 2 out of their 3 patients, which had not been previously reported (Baldridge et al, 2020). This constellation of features overlaps with both CHARGE syndrome and Kabuki syndrome but is distinct from both.…”

Section: Introductionmentioning

confidence: 55%

“…One group also noted the presence of interstitial lung disease in 2 out of their 3 patients, which had not been previously reported (Baldridge et al, 2020). This constellation of features overlaps with both CHARGE syndrome and Kabuki syndrome but is distinct from both.…”

mentioning

confidence: 64%

“…As many genetic disorders share overlapping features, phenotype delineation is crucial to guiding genetic testing and interpretation of results. For example, CHARGE syndrome, Kabuki syndrome, and a KMT2D allelic disorder distinct from Kabuki syndrome and described in two recent publications (Baldridge et al, 2020; Cuvertino et al, 2020) exhibit significant clinical overlap (Butcher et al, 2017; Verhagen et al, 2014), and distinguishing between them may be difficult, particularly since Kabuki syndrome and the KMT2D Ex 38/39 disorder are both caused by variants in KMT2D . However, the KMT2D Ex 38/39 disorder is caused by missense variants in a specific, highly conserved region spanning exons 38 and 39 and leads to features distinct from Kabuki syndrome.…”

Section: Introductionmentioning

confidence: 99%

“…However, it was recently discovered that some patients with overlapping phenotypic features but a known variant in KMT2D who were therefore thought to have a molecular diagnosis of Kabuki syndrome actually have a different disorder altogether. Unlike KMT2D variants leading to Kabuki syndrome, which are typically nonsense variants that subsequently lead to protein truncation and resultant haploinsufficiency (Faundes et al, 2019), this cluster of heterozygous KMT2D variants in a highly conserved key region of exons 38–39 were all missense and led to a distinct methylation pattern and therefore an epigenetically distinct disorder (Baldridge et al, 2020; Cuvertino et al, 2020). These patients' unique clinical features were most notable for choanal atresia, hypoplastic nipples, branchial apparatus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities.…”

Section: Introductionmentioning

confidence: 99%

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Neuroimaging in Kabuki syndrome and another KMT2D‐related disorder

Stadelmaier

Kenna

Barrett

et al. 2021

American J of Med Genetics Pt A

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Recognition of distinct phenotypic features is an important component of genetic diagnosis. Although CHARGE syndrome, Kabuki syndrome, and a recently delineated KMT2D Ex 38/39 allelic disorder exhibit significant overlap, differences on neuroimaging may help distinguish these conditions and guide genetic testing and variant interpretation. We present an infant clinically diagnosed with CHARGE syndrome but subsequently found to have a de novo missense variant in exon 38 of KMT2D, the gene implicated in both Kabuki syndrome and a distinct KMT2D allelic disorder.We compare her brain and inner ear morphology to a retrospective cohort of 21 patients with classic Kabuki syndrome and to typical CHARGE syndrome findings described in the literature. Thirteen of the 21 Kabuki syndrome patients had temporal bone imaging (5/13 CT, 12/13 MRI) and/or brain MRI (12/13) which revealed findings distinct from both CHARGE syndrome and the KMT2D allelic disorder. Our findings further elucidate the spectrum of inner ear dysmorphology distinguishing Kabuki syndrome and the KMT2D allelic disorder from CHARGE syndrome, suggesting that these three disorders may be differentiated at least in part by their inner ear anomalies.

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Section: Introductionmentioning

confidence: 55%

mentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuroimaging in Kabuki syndrome and another KMT2D‐related disorder

Stadelmaier

Kenna

Barrett

et al. 2021

American J of Med Genetics Pt A

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“…Severe sJIA-LD was found in another patient with Kabuki syndrome related to KMT2D defect. Severe interstitial lung disease was recently reported in two patients with de novo KMT2D missense variants, suggesting the possible role of KMT2D defect in sJIA-LD [6] . Based on limited cases in this study, it is hard to conclude the association of sJIA-LD and anaphylaxis to tocilizumab.…”

Section: Discussionmentioning

confidence: 94%

Pulmonary involvements in systemic juvenile arthritis

He¹,

Ling²,

Yang³

2020

Preprint

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Background Systemic juvenile idiopathic arthritis (sJIA) is a chronic inflammatory disease of childhood. Pulmonary involvements in sJIA have been recently described. Herein, we assess unusual clinical and radiological features of patients with sJIA, and possible risk factors for pulmonary involvements in sJIA. Methods A total of thirty-nine patients with sJIA were retrospectively enrolled. Data extracted included demographics, medical history, clinical manifestations, laboratory results, serum cytokine levels, radiological findings, management, and prognosis. Results Macrophage activation syndrome (MAS) had been observed at the initial diagnosis or during disease flares in eleven patients (11/39, 28%). Cerebral venous sinus thrombosis was observed in one patient with paroxysmal headache during the MAS phase. Twenty-three patients demonstrated abnormal radiological features on chest Computed Tomography (CT). Only eleven patients had subtle respiratory symptoms with normal oxygen saturation. Eight patients had lung disease (LD) before biologic exposure. sJIA-LD occurred in another six patients after the introduction of tocilizumab. All these patients continued to receive tocilizumab therapy, and sJIA-LD was improved in twelve patients with complete resolution of pulmonary presentations, and partially relieved in two patients. Only one of the two patients with possible anaphylaxis to tocilizumab presented with LD. Severe sJIA-LD was found in two patients with trisomy 21 and Kabuki syndrome, respectively. Conclusions Pulmonary involvements are increasingly observed in children with sJIA. Possible high risks for sJIA-LD include the occurrence of MAS, some inherited diseases, and evidence of drug hypersensitivity. It is still a question of whether IL-1/IL-6 inhibitor exposure increases the risk of sJIA-LD. Vasculitis and thrombosis should be considered in sJIA during the MAS phase, particularly in patients with pulmonary involvements. Trial registration: Not applicable; this was a retrospective study.

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Refining the clinical phenotype associated with missense variants in exons 38 and 39 of KMT2D

Tharreau¹,

Garde

Marlin

et al. 2022

American J of Med Genetics Pt A

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Loss‐of‐function variants in KMT2D are responsible for Kabuki syndrome type 1 (KS1). In the last 5 years, missense variants in exon 38 or 39 in KMT2D have been found in patients exhibiting a new phenotype with multiple malformations and absence of intellectual disability, distinct from KS1. To date, only 16 cases have been reported with classic features of hearing loss, abnormality of the ear, lacrimal duct defects, branchial sinus/neck pits, choanal atresia (CA), athelia, hypo(para)thyroidism, growth delay, and dental anomalies. We report here two families and one unpublished variant, refining the clinical and molecular knowledge on this new entity. Family 1 presented with apparently isolated autosomal dominant choanal atresia, in eight members across three generations. Exome sequencing (ES) in the proband and one cousin revealed a p.Glu3569Gly variant in exon 38 of KMT2D, segregating with choanal atresia in the family. Clinical reevaluation evidenced thyroid dysfunction, mild hearing anomalies, and hypoplastic nipple in some patients. Family 2 presented with nasolacrimal duct obstruction, hearing loss, mild facial features, unilateral axial polydactyly, and unilateral toe V‐VI syndactyly. ES revealed a de novo already reported p.Arg3582Gln variant in exon 38 of KMT2D. Considering these results and the existing literature, we suspect that missense variants in exon 38 of KMT2D are responsible for phenotypes that are even milder (isolated CA) and broader (polydactyly) than what has been previously described.

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Phenotypic expansion of KMT2D‐related disorder: Beyond Kabuki syndrome

Cited by 26 publications

References 62 publications

Neuroimaging in Kabuki syndrome and another KMT2D‐related disorder

Neuroimaging in Kabuki syndrome and another KMT2D‐related disorder

Pulmonary involvements in systemic juvenile arthritis

Refining the clinical phenotype associated with missense variants in exons 38 and 39 of KMT2D

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