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Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

Ockeloen CW, Willemsen MH, de Munnik S, van Bon BW, de Leeuw N, Verrips A, Kant SG, Jones EA, Brunner HG, van Loon RL, Smeets EE, van Haelst MM, van Haaften G, Nordgren A, Malmgren H, Grigelioniene G, Vermeer S, Louro P, Ramos L, Maal TJ, van Heumen CC, Yntema HG, Carels CE, Kleefstra T - Eur. J. Hum. Genet. (2014)

Bottom Line: Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity.Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent.As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

No MeSH data available.


Related in: MedlinePlus

Clinical features of families 1–11 with ANKRD11 mutations. a=1A, b=1B, c=1C, d=1D, e=1E, f=2, g=3, h=4, i=5, j=6, k=7A, l=7B, m=7C, n=8, o=9, p=10, q=11, r=12A, s=12B. The facial shape seems to evolve from round to more triangular at a later age, as seen in patient 5 (i), 7A (k) and 7C (m). All patients have an upturned nose with a broad base to the nose and full nasal tip. Other characteristic features are broad or bushy eyebrows with synophrys, strikingly prominent eyelashes (g, h, k, n, o), a low posterior hairline, brachy/turricephaly, a long philtrum, hypertelorism and prominent or protruding ears with dysplastic helices. Some patients have an exaggerated cupid's bow-shaped mouth (a, i, k, m, n, o) but other patients have a thin upper lip (e, h, l, p, s). The hair can be coarse (a, b, d, l, q).
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fig1: Clinical features of families 1–11 with ANKRD11 mutations. a=1A, b=1B, c=1C, d=1D, e=1E, f=2, g=3, h=4, i=5, j=6, k=7A, l=7B, m=7C, n=8, o=9, p=10, q=11, r=12A, s=12B. The facial shape seems to evolve from round to more triangular at a later age, as seen in patient 5 (i), 7A (k) and 7C (m). All patients have an upturned nose with a broad base to the nose and full nasal tip. Other characteristic features are broad or bushy eyebrows with synophrys, strikingly prominent eyelashes (g, h, k, n, o), a low posterior hairline, brachy/turricephaly, a long philtrum, hypertelorism and prominent or protruding ears with dysplastic helices. Some patients have an exaggerated cupid's bow-shaped mouth (a, i, k, m, n, o) but other patients have a thin upper lip (e, h, l, p, s). The hair can be coarse (a, b, d, l, q).

Mentions: An overview of the clinical and molecular characteristics of families 1–12 is listed in Table 1 and Figure 1. All patients included in our study were clinically diagnosed with KBG syndrome compatible with the clinical criteria proposed by Skjei et al15 All our cases with normal array results were molecularly confirmed by the detection of heterozygous loss-of-function variants in ANKRD11. Table 2 shows the clinical features of patient 13 with a 1.16 Mb deletion encompassing exons 3–13 of the ANKRD11 gene (arr(hg19) 16q24.3(88231090–89388103) × 1) and an overview of the features of ANKRD11 microdeletion patients reported previously in other studies.2, 3, 5, 6, 7, 8, 9, 10 In total, we identified 11 different loss-of-function variants in ANKRD11 (Table 1; genomebuild GRCh37 (hg19), NM001256182.1).


Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

Ockeloen CW, Willemsen MH, de Munnik S, van Bon BW, de Leeuw N, Verrips A, Kant SG, Jones EA, Brunner HG, van Loon RL, Smeets EE, van Haelst MM, van Haaften G, Nordgren A, Malmgren H, Grigelioniene G, Vermeer S, Louro P, Ramos L, Maal TJ, van Heumen CC, Yntema HG, Carels CE, Kleefstra T - Eur. J. Hum. Genet. (2014)

Clinical features of families 1–11 with ANKRD11 mutations. a=1A, b=1B, c=1C, d=1D, e=1E, f=2, g=3, h=4, i=5, j=6, k=7A, l=7B, m=7C, n=8, o=9, p=10, q=11, r=12A, s=12B. The facial shape seems to evolve from round to more triangular at a later age, as seen in patient 5 (i), 7A (k) and 7C (m). All patients have an upturned nose with a broad base to the nose and full nasal tip. Other characteristic features are broad or bushy eyebrows with synophrys, strikingly prominent eyelashes (g, h, k, n, o), a low posterior hairline, brachy/turricephaly, a long philtrum, hypertelorism and prominent or protruding ears with dysplastic helices. Some patients have an exaggerated cupid's bow-shaped mouth (a, i, k, m, n, o) but other patients have a thin upper lip (e, h, l, p, s). The hair can be coarse (a, b, d, l, q).
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Related In: Results  -  Collection

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fig1: Clinical features of families 1–11 with ANKRD11 mutations. a=1A, b=1B, c=1C, d=1D, e=1E, f=2, g=3, h=4, i=5, j=6, k=7A, l=7B, m=7C, n=8, o=9, p=10, q=11, r=12A, s=12B. The facial shape seems to evolve from round to more triangular at a later age, as seen in patient 5 (i), 7A (k) and 7C (m). All patients have an upturned nose with a broad base to the nose and full nasal tip. Other characteristic features are broad or bushy eyebrows with synophrys, strikingly prominent eyelashes (g, h, k, n, o), a low posterior hairline, brachy/turricephaly, a long philtrum, hypertelorism and prominent or protruding ears with dysplastic helices. Some patients have an exaggerated cupid's bow-shaped mouth (a, i, k, m, n, o) but other patients have a thin upper lip (e, h, l, p, s). The hair can be coarse (a, b, d, l, q).
Mentions: An overview of the clinical and molecular characteristics of families 1–12 is listed in Table 1 and Figure 1. All patients included in our study were clinically diagnosed with KBG syndrome compatible with the clinical criteria proposed by Skjei et al15 All our cases with normal array results were molecularly confirmed by the detection of heterozygous loss-of-function variants in ANKRD11. Table 2 shows the clinical features of patient 13 with a 1.16 Mb deletion encompassing exons 3–13 of the ANKRD11 gene (arr(hg19) 16q24.3(88231090–89388103) × 1) and an overview of the features of ANKRD11 microdeletion patients reported previously in other studies.2, 3, 5, 6, 7, 8, 9, 10 In total, we identified 11 different loss-of-function variants in ANKRD11 (Table 1; genomebuild GRCh37 (hg19), NM001256182.1).

Bottom Line: Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity.Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent.As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

No MeSH data available.


Related in: MedlinePlus