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Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS.

McDonald-McGinn DM, Fahiminiya S, Revil T, Nowakowska BA, Suhl J, Bailey A, Mlynarski E, Lynch DR, Yan AC, Bilaniuk LT, Sullivan KE, Warren ST, Emanuel BS, Vermeesch JR, Zackai EH, Jerome-Majewska LA - J. Med. Genet. (2012)

Bottom Line: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals.This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome.Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Genetics, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

ABSTRACT

Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000-4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype.

Methods: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals.

Results and conclusions: In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.

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Related in: MedlinePlus

Patient description. (1A) Patient 1— Anteroposterior (AP) photo demonstrating upslanting palpebral fissures with hooded eyelids and hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi; and a mandibular cleft. (1B) Lateral photo demonstrating auricular anomalies including thick crumpled helices with attached lobes. (1C) A 2 mm thick T1 axial image of the brain reveals pronounced under-opercularisation with very wide Sylvian fissures and bilateral thick finely nodular cortex, consistent with polymicrogyria, throughout the brain but being particularly thick in the insular regions. There is abnormal brain morphology with some gyri being small and some wide. Also, there is diminished white matter and there are multiple anomalous deep fissures in both parieto-occipital regions that extend near to and deform the atria of the lateral ventricles, particularly on the right. The genu of the corpus callosum is unusually thick and the splenium is very thin. (1D) A focal area of frictional alopecia on the vertex. (1E) Right foot displays a diffuse keratoderma with erythema and thick desquamating hyperkeratotic sheets localised to the plantar surface of the foot and toes. (1F) Right hand shows diffuse keratoderma with erythema and overlying desquamation on the palmar surface, notably sparing the dorsal aspects of the fingers and nails. Accentuated skin markings can be appreciated on the volar wrist. (2A) Patient 2—AP photo demonstrating mild upslanting palpebral fissures on the left and a bulbous nasal tip with hypoplastic alae nasi. (2B) Lateral photo demonstrating normally formed ears with attached lobes; a nasal dimple; and micrognathia. (2C) A 0.9 mm thick axial T1 weighted image at the level of the insulae shows pronounced under-opercularisation with open Sylvian fissures and bilateral extensive thick nodular cortex representing polymicrogyria in all lobes of the brain, but most prominent in the insulae and the brain posterior to them. There is diminished white matter and abnormal gyral pattern throughout the brain. Also noted are anomalous deep fissures lined by the thick nodular cortex extending near to the ventricular atria and deforming them, more on the right. The genu of the corpus callosum is seen and the splenium, being very thin, is not included on this section. (2D) Anterior trunk showing diffuse xerosis and a fine, powdery, ichthyosiform scale which is accentuated on the arms. (2E) Bilateral plantar feet reveal a diffuse, glossy, yellowish keratoderma (thickening of the skin) with decreased skin markings and focal areas of desquamation on the heels. (2F) Right hand shows a diffuse, yellow-orange keratoderma with focal areas of desquamation on the palms and fingertips. (3A) Patient 3—AP photo demonstrating upslanting palpebral fissures with hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi, a blunted nasal tip with a dimple; asymmetric crying facies; and a healed tracheostomy scar. (3B) Lateral photo demonstrating auricular anomalies including crumpled helices with attached lobes and micrognathia. (4A) Patient 4—AP photo demonstrating hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi; and a repaired bilateral cleft lip and palate. (4B) Lateral photo demonstrating attached ear lobes and micrognathia.
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JMEDGENET2012101320F1: Patient description. (1A) Patient 1— Anteroposterior (AP) photo demonstrating upslanting palpebral fissures with hooded eyelids and hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi; and a mandibular cleft. (1B) Lateral photo demonstrating auricular anomalies including thick crumpled helices with attached lobes. (1C) A 2 mm thick T1 axial image of the brain reveals pronounced under-opercularisation with very wide Sylvian fissures and bilateral thick finely nodular cortex, consistent with polymicrogyria, throughout the brain but being particularly thick in the insular regions. There is abnormal brain morphology with some gyri being small and some wide. Also, there is diminished white matter and there are multiple anomalous deep fissures in both parieto-occipital regions that extend near to and deform the atria of the lateral ventricles, particularly on the right. The genu of the corpus callosum is unusually thick and the splenium is very thin. (1D) A focal area of frictional alopecia on the vertex. (1E) Right foot displays a diffuse keratoderma with erythema and thick desquamating hyperkeratotic sheets localised to the plantar surface of the foot and toes. (1F) Right hand shows diffuse keratoderma with erythema and overlying desquamation on the palmar surface, notably sparing the dorsal aspects of the fingers and nails. Accentuated skin markings can be appreciated on the volar wrist. (2A) Patient 2—AP photo demonstrating mild upslanting palpebral fissures on the left and a bulbous nasal tip with hypoplastic alae nasi. (2B) Lateral photo demonstrating normally formed ears with attached lobes; a nasal dimple; and micrognathia. (2C) A 0.9 mm thick axial T1 weighted image at the level of the insulae shows pronounced under-opercularisation with open Sylvian fissures and bilateral extensive thick nodular cortex representing polymicrogyria in all lobes of the brain, but most prominent in the insulae and the brain posterior to them. There is diminished white matter and abnormal gyral pattern throughout the brain. Also noted are anomalous deep fissures lined by the thick nodular cortex extending near to the ventricular atria and deforming them, more on the right. The genu of the corpus callosum is seen and the splenium, being very thin, is not included on this section. (2D) Anterior trunk showing diffuse xerosis and a fine, powdery, ichthyosiform scale which is accentuated on the arms. (2E) Bilateral plantar feet reveal a diffuse, glossy, yellowish keratoderma (thickening of the skin) with decreased skin markings and focal areas of desquamation on the heels. (2F) Right hand shows a diffuse, yellow-orange keratoderma with focal areas of desquamation on the palms and fingertips. (3A) Patient 3—AP photo demonstrating upslanting palpebral fissures with hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi, a blunted nasal tip with a dimple; asymmetric crying facies; and a healed tracheostomy scar. (3B) Lateral photo demonstrating auricular anomalies including crumpled helices with attached lobes and micrognathia. (4A) Patient 4—AP photo demonstrating hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi; and a repaired bilateral cleft lip and palate. (4B) Lateral photo demonstrating attached ear lobes and micrognathia.

Mentions: Patient 1 presented with a history of laryngotracheomalacia, a small patent ductus arteriosus, gastro-oesophageal reflux disease, failure to thrive and feeding difficulty requiring G-tube placement, chronic infection, polymicrogyria, and dysmorphic features including hypertelorism. In addition, he had: microcephaly, strabismus, optic nerve hypoplasia, bilateral sensorineural hearing loss, obstructive sleep apnoea, immunoglobulin G (IgG) and IgM deficiency, a unilateral inguinal hernia and undescended testis. More recently, he was noted to have palmoplantar keratoderma and ichthyosis, (figure 1: 1A–F). The homozygous frameshift insertion within SNAP29, c.388_389insGA (p.T130fs), has not previously been seen in dbSNP, 1000 Genomes Project or EVS, and was subsequently confirmed by Sanger sequencing (figure 2A–C). Sanger sequencing of parental blood DNA revealed a heterozygous insertion in the father at the same position (figure 2C), suggesting that the proband was hemizygous for the 22q11.2 chromosome, as determined by fluorescence in situ hybridisation. (FISH), and inherited a non-functional SNAP29 gene from the father and by inference a de novo deletion on the 22q11.2 chromosome inherited from his mother. Truncating mutations in SNAP29 are associated with CEDNIK syndrome, an autosomal recessive condition characterised by cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma.1415 The frameshift mutation identified in SNAP29 is predicted to result in a truncated protein with 129 amino acids of the SNAP29 protein, and insertion of 17 novel amino acids before a premature stop (figure 2C).


Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS.

McDonald-McGinn DM, Fahiminiya S, Revil T, Nowakowska BA, Suhl J, Bailey A, Mlynarski E, Lynch DR, Yan AC, Bilaniuk LT, Sullivan KE, Warren ST, Emanuel BS, Vermeesch JR, Zackai EH, Jerome-Majewska LA - J. Med. Genet. (2012)

Patient description. (1A) Patient 1— Anteroposterior (AP) photo demonstrating upslanting palpebral fissures with hooded eyelids and hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi; and a mandibular cleft. (1B) Lateral photo demonstrating auricular anomalies including thick crumpled helices with attached lobes. (1C) A 2 mm thick T1 axial image of the brain reveals pronounced under-opercularisation with very wide Sylvian fissures and bilateral thick finely nodular cortex, consistent with polymicrogyria, throughout the brain but being particularly thick in the insular regions. There is abnormal brain morphology with some gyri being small and some wide. Also, there is diminished white matter and there are multiple anomalous deep fissures in both parieto-occipital regions that extend near to and deform the atria of the lateral ventricles, particularly on the right. The genu of the corpus callosum is unusually thick and the splenium is very thin. (1D) A focal area of frictional alopecia on the vertex. (1E) Right foot displays a diffuse keratoderma with erythema and thick desquamating hyperkeratotic sheets localised to the plantar surface of the foot and toes. (1F) Right hand shows diffuse keratoderma with erythema and overlying desquamation on the palmar surface, notably sparing the dorsal aspects of the fingers and nails. Accentuated skin markings can be appreciated on the volar wrist. (2A) Patient 2—AP photo demonstrating mild upslanting palpebral fissures on the left and a bulbous nasal tip with hypoplastic alae nasi. (2B) Lateral photo demonstrating normally formed ears with attached lobes; a nasal dimple; and micrognathia. (2C) A 0.9 mm thick axial T1 weighted image at the level of the insulae shows pronounced under-opercularisation with open Sylvian fissures and bilateral extensive thick nodular cortex representing polymicrogyria in all lobes of the brain, but most prominent in the insulae and the brain posterior to them. There is diminished white matter and abnormal gyral pattern throughout the brain. Also noted are anomalous deep fissures lined by the thick nodular cortex extending near to the ventricular atria and deforming them, more on the right. The genu of the corpus callosum is seen and the splenium, being very thin, is not included on this section. (2D) Anterior trunk showing diffuse xerosis and a fine, powdery, ichthyosiform scale which is accentuated on the arms. (2E) Bilateral plantar feet reveal a diffuse, glossy, yellowish keratoderma (thickening of the skin) with decreased skin markings and focal areas of desquamation on the heels. (2F) Right hand shows a diffuse, yellow-orange keratoderma with focal areas of desquamation on the palms and fingertips. (3A) Patient 3—AP photo demonstrating upslanting palpebral fissures with hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi, a blunted nasal tip with a dimple; asymmetric crying facies; and a healed tracheostomy scar. (3B) Lateral photo demonstrating auricular anomalies including crumpled helices with attached lobes and micrognathia. (4A) Patient 4—AP photo demonstrating hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi; and a repaired bilateral cleft lip and palate. (4B) Lateral photo demonstrating attached ear lobes and micrognathia.
© Copyright Policy - open-access
Related In: Results  -  Collection

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JMEDGENET2012101320F1: Patient description. (1A) Patient 1— Anteroposterior (AP) photo demonstrating upslanting palpebral fissures with hooded eyelids and hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi; and a mandibular cleft. (1B) Lateral photo demonstrating auricular anomalies including thick crumpled helices with attached lobes. (1C) A 2 mm thick T1 axial image of the brain reveals pronounced under-opercularisation with very wide Sylvian fissures and bilateral thick finely nodular cortex, consistent with polymicrogyria, throughout the brain but being particularly thick in the insular regions. There is abnormal brain morphology with some gyri being small and some wide. Also, there is diminished white matter and there are multiple anomalous deep fissures in both parieto-occipital regions that extend near to and deform the atria of the lateral ventricles, particularly on the right. The genu of the corpus callosum is unusually thick and the splenium is very thin. (1D) A focal area of frictional alopecia on the vertex. (1E) Right foot displays a diffuse keratoderma with erythema and thick desquamating hyperkeratotic sheets localised to the plantar surface of the foot and toes. (1F) Right hand shows diffuse keratoderma with erythema and overlying desquamation on the palmar surface, notably sparing the dorsal aspects of the fingers and nails. Accentuated skin markings can be appreciated on the volar wrist. (2A) Patient 2—AP photo demonstrating mild upslanting palpebral fissures on the left and a bulbous nasal tip with hypoplastic alae nasi. (2B) Lateral photo demonstrating normally formed ears with attached lobes; a nasal dimple; and micrognathia. (2C) A 0.9 mm thick axial T1 weighted image at the level of the insulae shows pronounced under-opercularisation with open Sylvian fissures and bilateral extensive thick nodular cortex representing polymicrogyria in all lobes of the brain, but most prominent in the insulae and the brain posterior to them. There is diminished white matter and abnormal gyral pattern throughout the brain. Also noted are anomalous deep fissures lined by the thick nodular cortex extending near to the ventricular atria and deforming them, more on the right. The genu of the corpus callosum is seen and the splenium, being very thin, is not included on this section. (2D) Anterior trunk showing diffuse xerosis and a fine, powdery, ichthyosiform scale which is accentuated on the arms. (2E) Bilateral plantar feet reveal a diffuse, glossy, yellowish keratoderma (thickening of the skin) with decreased skin markings and focal areas of desquamation on the heels. (2F) Right hand shows a diffuse, yellow-orange keratoderma with focal areas of desquamation on the palms and fingertips. (3A) Patient 3—AP photo demonstrating upslanting palpebral fissures with hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi, a blunted nasal tip with a dimple; asymmetric crying facies; and a healed tracheostomy scar. (3B) Lateral photo demonstrating auricular anomalies including crumpled helices with attached lobes and micrognathia. (4A) Patient 4—AP photo demonstrating hypertelorism; malar flatness; a bulbous nasal tip with hypoplastic alae nasi; and a repaired bilateral cleft lip and palate. (4B) Lateral photo demonstrating attached ear lobes and micrognathia.
Mentions: Patient 1 presented with a history of laryngotracheomalacia, a small patent ductus arteriosus, gastro-oesophageal reflux disease, failure to thrive and feeding difficulty requiring G-tube placement, chronic infection, polymicrogyria, and dysmorphic features including hypertelorism. In addition, he had: microcephaly, strabismus, optic nerve hypoplasia, bilateral sensorineural hearing loss, obstructive sleep apnoea, immunoglobulin G (IgG) and IgM deficiency, a unilateral inguinal hernia and undescended testis. More recently, he was noted to have palmoplantar keratoderma and ichthyosis, (figure 1: 1A–F). The homozygous frameshift insertion within SNAP29, c.388_389insGA (p.T130fs), has not previously been seen in dbSNP, 1000 Genomes Project or EVS, and was subsequently confirmed by Sanger sequencing (figure 2A–C). Sanger sequencing of parental blood DNA revealed a heterozygous insertion in the father at the same position (figure 2C), suggesting that the proband was hemizygous for the 22q11.2 chromosome, as determined by fluorescence in situ hybridisation. (FISH), and inherited a non-functional SNAP29 gene from the father and by inference a de novo deletion on the 22q11.2 chromosome inherited from his mother. Truncating mutations in SNAP29 are associated with CEDNIK syndrome, an autosomal recessive condition characterised by cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma.1415 The frameshift mutation identified in SNAP29 is predicted to result in a truncated protein with 129 amino acids of the SNAP29 protein, and insertion of 17 novel amino acids before a premature stop (figure 2C).

Bottom Line: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals.This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome.Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Genetics, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

ABSTRACT

Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000-4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype.

Methods: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals.

Results and conclusions: In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.

Show MeSH
Related in: MedlinePlus