RESUMEN

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GPS) are caused by variants of lysine acetyltransferase 6B (KAT6B). These variants tend to occur in the terminal exons of KAT6B. Here, we report a patient with global developmental delay, intellectual disability, autistic behavior, muscular hypotonia, facial dysmorphism, and seizures caused by a novel missense variant in exon 7 of KAT6B. The patient showed a phenotype differing from those of SBBYSS and GPS. We also report patients with missense variants in the proximal exons of KAT6B showing dysmorphic features and autistic behavior not resembling the characteristics of SBBYSS and GPS. Missense variants in the proximal exons of KAT6B may have a dominant negative effect or cause gain of function, leading to unique phenotypes not resembling those of SBBYSS and GPS.

RESUMEN

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

Asunto(s)

Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Histona Acetiltransferasas/genética , Mutación , Fenotipo , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Alelos , Blefarofimosis/diagnóstico , Blefarofimosis/genética , Estudios de Cohortes , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/genética , Facies , Asesoramiento Genético , Sitios Genéticos , Genotipo , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Riñón/anomalías , Masculino , Rótula/anomalías , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/genética , Escroto/anomalías , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genética

RESUMEN

A patient with global developmental delay and facial abnormality treated in Hunan Maternal and Child Health Care Hospital in September 2018 was diagnosed as a typical Say-Barber-Biesecker/Young-Simpson syndrome (SBBYSS)accompanied with comprehensive clinical manifestations and genetic testing was carried out.The patient carries a heterozygous synonymous mutation of KAT6B gene (NM_012330.3)c.3147G>A (p.P1049P), thus leading to the formation of a new cleavage site (receptor) and forming a new truncated protein.In Chinese, this is the second typical SBBYSS that has been identified and the first prenatal genetic diagnosis has been performed.This study has broadened the mutation spectrum of SBBYSS caused by the mutation of KAT6B gene in Chinese population.

RESUMEN

PURPOSE: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. METHODS: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. RESULTS: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. CONCLUSION: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

Asunto(s)

Blefarofimosis , Discapacidad Intelectual , Blefarofimosis/genética , Exones , Histona Acetiltransferasas/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Mutación

RESUMEN

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are very rare conditions caused by KAT6B truncating variants. Because of both syndromes often share common features the associated phenotypes are usually grouped under the term "KAT6B-related disorders." However, particular signs of each syndrome have been reported and their appearance seems to be dependent on where the KAT6B variant is located. Thus, whereas truncating variants associated with SBBYSS have their highest density in the distal part of exon 18, those resulting in GTPTS are distributed between the end of exon 17 and beginning of exon 18. Here, we reported two de novo heterozygous KAT6B truncating variants. The first variant (c.5802delA; p.A1935Pfs*16), identified in a boy with SSBYSS phenotype, resulting in the most distal KAT6B truncating variant reported up-to-date in the scientific literature. The second variant (c.3152delG; p.S1051Tfs*63), located in a region hitherto defined as specific of SBBYSS, seems to cause an overlapping SBBYSS/GTPTS phenotype. The clinical and genetic characterization of these patients could contribute to the understanding of the KAT6B-related disorders.

Asunto(s)

Anomalías Múltiples/genética , Blefarofimosis/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Cardiopatías Congénitas/genética , Histona Acetiltransferasas/genética , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/genética , Riñón/anomalías , Rótula/anomalías , Trastornos Psicomotores/genética , Escroto/anomalías , Anomalías Urogenitales/genética , Anomalías Múltiples/fisiopatología , Blefarofimosis/fisiopatología , Niño , Hipotiroidismo Congénito/fisiopatología , Anomalías Craneofaciales/fisiopatología , Exones/genética , Facies , Cardiopatías Congénitas/fisiopatología , Heterocigoto , Humanos , Discapacidad Intelectual/fisiopatología , Inestabilidad de la Articulación/fisiopatología , Riñón/fisiopatología , Masculino , Mutación , Rótula/fisiopatología , Fenotipo , Trastornos Psicomotores/fisiopatología , Escroto/fisiopatología , Anomalías Urogenitales/fisiopatología

RESUMEN

The Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are 2 rare but clinically well-described diseases caused by de novo heterozygous sequence variants in the KAT6B gene. Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities, and patellar hypoplasia/agenesis. In addition, congenital heart defects, dental abnormalities, hearing loss, and thyroid anomalies are common to both phenotypes. This broad clinical overlap led some authors to propose the concept of KAT6B spectrum disorders. On the other hand, some clinical features could help to differentiate the 2 disorders. Furthermore, it is possible to establish a genotype-phenotype correlation when considering the position of the sequence variant along the gene, supporting the notion of the 2 disorders as really distinct entities.

Asunto(s)

Blefarofimosis/diagnóstico , Blefarofimosis/etiología , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/etiología , Susceptibilidad a Enfermedades , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/etiología , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/etiología , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/etiología , Alelos , Biomarcadores , Diagnóstico Diferencial , Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Fenotipo

RESUMEN

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GTPTS) are clinically similar disorders with some overlapping features. Although they are currently considered to be distinct clinical entities, both were found to be caused by de novo truncating sequence variants in the KAT6B (lysine acetyltransferase 6B) gene, strongly suggesting that they are allelic disorders. Herein, we report the clinical and genetic findings in a girl presenting with a serious multiple congenital anomaly syndrome with phenotypic features overlapping both SBBYSS and GTPTS; pointing out that the clinical distinction between these disorders is not exact and there do exist patients, in whom conventional clinical classification is problematic. Genetic analyses revealed a truncating c.4592delA (p.Asn1531Thrfs*18) variant in the last KAT6B exon. Our findings support that phenotypes associated with typical KAT6B disease-causing variants should be referred to as 'KAT6B spectrum disorders' or 'KAT6B related disorders', rather than their current SBBYSS and GTPTS classification.

Asunto(s)

Anomalías Múltiples/diagnóstico , Blefarofimosis/diagnóstico , Hipotiroidismo Congénito/diagnóstico , Anomalías Craneofaciales/diagnóstico , Cardiopatías Congénitas/diagnóstico , Histona Acetiltransferasas/genética , Discapacidad Intelectual/diagnóstico , Inestabilidad de la Articulación/diagnóstico , Riñón/anomalías , Rótula/anomalías , Trastornos Psicomotores/diagnóstico , Escroto/anomalías , Anomalías Urogenitales/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Blefarofimosis/genética , Blefarofimosis/patología , Preescolar , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/patología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Exones , Facies , Femenino , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/patología , Riñón/patología , Mutación , Rótula/patología , Fenotipo , Trastornos Psicomotores/genética , Trastornos Psicomotores/patología , Escroto/patología , Anomalías Urogenitales/genética , Anomalías Urogenitales/patología

RESUMEN

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are two distinct clinically overlapping syndromes caused by de novo heterozygous truncating mutations in the KAT6B gene encoding lysine acetyltransferase 6B, a part of the histone H3 acetyltransferase complex. We describe an 8-year-old girl with a KAT6B mutation and a combined GPS/SBBYSS phenotype. The comparison of this patient with 61 previously published cases with KAT6B mutations and GPS, SBBYSS or combined GPS/SBBYSS phenotypes allowed us to separate the KAT6B mutations into four groups according to their position in the gene (reflecting nonsense mediated RNA decay and protein domains) and their clinical outcome. We suggest that mutations in mid-exon 18 corresponding to the C-terminal end of the acidic (Asp/Glu-rich) domain of KAT6B may have more variable expressivity leading to GPS, SBBYSS or combined phenotypes, in contrast to defects in other regions of the gene which contribute more specifically to either GPS or SBBYSS. Notwithstanding the clinical overlap, our cluster analysis of phenotypes of all known patients with KAT6B mutations supports the existence of two clinical entities, GPS and SBBYSS, as poles within the KAT6B-related disease spectrum. The awareness of these phenomena is important for qualified genetic counselling of patients with KAT6B mutations.

Asunto(s)

Blefarofimosis/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Exones , Cardiopatías Congénitas/genética , Histona Acetiltransferasas/genética , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/genética , Riñón/anomalías , Mutación , Rótula/anomalías , Trastornos Psicomotores/genética , Escroto/anomalías , Anomalías Urogenitales/genética , Secuencia de Bases , Blefarofimosis/diagnóstico , Niño , Hipotiroidismo Congénito/diagnóstico , Anomalías Craneofaciales/diagnóstico , Facies , Femenino , Cardiopatías Congénitas/diagnóstico , Humanos , Discapacidad Intelectual/diagnóstico , Inestabilidad de la Articulación/diagnóstico , Datos de Secuencia Molecular , Fenotipo , Trastornos Psicomotores/diagnóstico , Anomalías Urogenitales/diagnóstico