Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3

Kutkowska-Kaźmierczak, Anna; Boczar, Maria; Kalka, Ewa; Castañeda, Jennifer; Klapecki, Jakub; Pietrzyk, Aleksandra; Barczyk, A.; Malinowska, Olga; Landowska, Aleksandra; Gambin, Tomasz; Kowalczyk, Katarzyna; Wiśniowiecka‐Kowalnik, Barbara; Smyk, Marta; Dawidziuk, Mateusz; Niepokój, Katarzyna; Paczkowska, Magdalena; Szyld, Paweł; Lipska‐Ziętkiewicz, Beata S.; Szczałuba, Krzysztof; Kostyk, Ewa; Runge, Agata; Rutkowska, Karolina; Płoski, Rafał; Nowakowska, Beata; Bal, Jerzy; Obersztyn, Ewa; Goś, Monika

doi:10.3390/genes12081257

Cited by 13 publications

(13 citation statements)

References 23 publications

(33 reference statements)

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“…This variant was initially classified as a variant of uncertain significance as it had not been previously reported at the time of sequencing, but it is now being reclassified because of new information available: two additional patients carrying the exact same variant. The Arg2536Gln variant has been also recently reported in an unrelated patient affected with KBG syndrome, as a de novo event [13]. This patient has the following clinical features: poor weight gain, feeding problems and wide fontanel/delayed closure.…”

Section: Resultsmentioning

confidence: 83%

KBG Syndrome: Prospective Videoconferencing and Use of AI-driven Facial Phenotyping in 25 New Patients

Guo

Park

et al. 2021

Preprint

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Genetic variants in the gene Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families, all with molecularly confirmed diagnoses of KBG syndrome. Twenty-one individuals have de novo variants, three have inherited variants, and one is inherited from a parent exhibiting low-level mosaicism. Of these variants, 20 are truncating (frameshift or nonsense), and five are missense. We created a novel protocol for collection and reporting of data, including prospectively interviewing these individuals and their families throughout eight countries via videoconferencing by a single clinician. Participants’ medical records, including imaging, were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were submitted to GestaltMatcher and Face2Gene (FDNA Inc, USA) for facial analysis, and we found similar facial phenotypes among the participants. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Seventy-two percent of participants had gastrointestinal complaints and 80% had hearing loss. Three participants were started on growth hormone with positive results. Behavioral issues and global developmental delays were found in most participants. Neurologic abnormalities including seizures and/or EEG abnormalities were also very common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Twenty-four percent were diagnosed with attention deficit hyperactivity disorder (ADHD) and 28% were diagnosed with autism spectrum disorder (ASD). Additionally, we have identified minimally reported symptoms, including recurrent sinus infections (16%) and previously unreported migraines (20%). Based on the videoconferencing and these data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

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Section: Resultsmentioning

confidence: 83%

KBG Syndrome: Prospective Videoconferencing and Use of AI-driven Facial Phenotyping in 25 New Patients

Guo

Park

et al. 2021

Preprint

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“…With the advent of the use of high-resolution CMA with specific NDD-enriched regions, several submicroscopic rearrangements in ANKRD11 are now emerging [ 23 ], as identified in PT12, who bears a 682 bp deletion. Most of the small deletions fall in non-coding regions of the gene, namely the first introns or the promoter region (CpG 205), suggesting their proneness to genomic rearrangements.…”

Section: Discussionmentioning

confidence: 99%

“…Given the molecular spectrum and broad phenotypic variability of KBGS, the optimal diagnostic approach is via multi-testing based on ANKRD11 sequencing—by single gene test or multi-gene panels—and chromosome microarray analysis (CMA) [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome

Bestetti

Crippa

Sironi

et al. 2022

IJMS

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KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 (ANKRD11) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11. A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients.

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“…This could explain the high prevalence of ADHD in our sample compared to that from the 273 patients from the literature. Nevertheless, a recent study by Kutkowska-Kazmierczak and colleagues described that 86% of the 23 patients reported had "psychomotor hyperactivity" and proposed to include these symptoms in the diagnostic criteria of KBG syndrome [13].…”

Section: Discussionmentioning

confidence: 99%

“…However, the clinical presentation of the syndrome is highly heterogeneous regarding both the phenotype and severity of the symptoms, with variable expressivity and penetrance [10]. This has resulted in a lack of a consensus clinical diagnostic criteria, with manifestations considered major and minor changing as new patients have been published [6][7][8][9][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: Addition of 67 new patients

Fernández-Jaén

Ayuso

Almoguera

2022

Preprint

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SUMMARYBackgroundKBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been published. Both loss-of-function sequence variants and large deletions (CNVs) involving ANKRD11 have been involved in KBG, but no genotype-phenotype correlation has been reported to date. This study presents the clinical and molecular characteristics of 67 new patients with KBG syndrome and the results of the first genotype-phenotype correlation leveraging data on 273 patients previously published.Methods67 patients with KBG syndrome were recruited through a Spanish collaborative effort and were assessed using a custom phenotypic questionnaire. The frequency of all features was calculated. Manifestations present in >50% of the patients and a “severity score” were used to perform a genotype-phenotype correlation in the 340 KBG patients.ResultsNeurodevelopmental delay (95%), comorbidites (82.8%), macrodontia (80.9%), triangular face (71%), characteristic ears (76%), nose (75.9%) and eyebrows (67.3%) were the most prevalent features in the 67 patients. The genotype-phenotype correlation yielded significant associations with the triangular face (71.1% in patients with sequence variants vs 45.2% in CNVs, p=0.015), short stature (62.5% variants in exon 9 vs. 27.8% outside; p=0.009) and macrodontia (with larger deletions, p=0.028), ID/ADHD/ASD (70.4% in c.1903_1907del vs. 89.4%; p=0.012) and a higher phenotypic score in patients with sequence variants compared with CNVs (p=0.005).ConclusionsWe present a detailed phenotypic description of KBG syndrome in the largest series of patients reported to date, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 aberrations, and propose updated clinical diagnostic criteria based on our findings.

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Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3

Cited by 13 publications

References 23 publications

KBG Syndrome: Prospective Videoconferencing and Use of AI-driven Facial Phenotyping in 25 New Patients

KBG Syndrome: Prospective Videoconferencing and Use of AI-driven Facial Phenotyping in 25 New Patients

Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: Addition of 67 new patients

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