Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

General Information (adopted from Orphanet):

Synonyms, Signs: SCN4
SCN4 Dursun syndrome, included
Pulmonary arterial hypertension, leukopenia, and atrial septal defect, included
Severe congenital neutropenia 4
Severe congenital neutropenia - pulmonary hypertension - superficial venous angiectasis
Number of Symptoms 85
OrphanetNr: 331176
OMIM Id: 612541
ICD-10: D70
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: < 0.1 of 100 000 [Orphanet]
Inheritance: Autosomal recessive
20717171 [IBIS]
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: Severe congenital neutropenia
 -Rare genetic disease
 -Rare immune disease

Comment:

Comparing to Glycogen storage disease Ib (OMIM:232220, Orpha:79259) this disease was named GSD-I related syndrome (GSD-Irs) (PMID:25288127). G6Pase-beta (G6PC3) deficiency is not a glycogen storage disease but biochemically it is a GSD-I related syndrome (GSD-Irs). The mechanism underlying clinical neutropenia and myeloid dysfunction in patients with GSD-Ib and GSD-Irs results from a defective G6Pase-beta (G6PC3)/G6PT complex in myeloid tissues. One underlying cause of neutrophil/macrophage dysfunction in GSD-Ib and GSD-Irs is a disturbance in ER energy homeostasis caused by a loss of G6Pase-beta (G6PC3)/G6PT-mediated glucose/G6P recycling (PMID:25288127). The structural and functional similarities between the two phosphatases alpha and beta (G6PC and G6PC3) would suggest that W59R, p.R253C, and p.L325R mutations are pathogenic (PMID:25492228).

Symptom Information: Sort by abundance 

1
(HPO:0000104) Renal agenesis 20717171 IBIS 68 / 7739
2
(HPO:0000126) Hydronephrosis 23056709 IBIS 119 / 7739
3
(HPO:0000058) Abnormality of the labia 22050868 IBIS 1 / 7739
4
(HPO:0008689) Bilateral cryptorchidism 24796372 IBIS 38 / 7739
5
(HPO:0000089) Renal hypoplasia 22050868 IBIS 78 / 7739
6
(HPO:0000122) Unilateral renal agenesis 20717171 IBIS 24 / 7739
7
(HPO:0000028) Cryptorchidism Frequent [IBIS] 52% (n=33) 23171239 IBIS 347 / 7739
8
(HPO:0000054) Micropenis 25391451 IBIS 257 / 7739
9
(HPO:0000815) Hypergonadotropic hypogonadism 25391451 IBIS 48 / 7739
10
(HPO:0010958) Bilateral renal agenesis 22050868 IBIS 16 / 7739
11
(HPO:0100540) Palpebral edema 23441086 IBIS 31 / 7739
12
(HPO:0000272) Malar flattening 25391451 IBIS 277 / 7739
13
(HPO:0000175) Cleft palate 20717171 IBIS 349 / 7739
14
(HPO:0000303) Mandibular prognathia 23171239 IBIS 179 / 7739
15
(HPO:0011107) Recurrent aphthous stomatitis 25391451 IBIS 13 / 7739
16
(HPO:0000431) Wide nasal bridge 22050868 IBIS 290 / 7739
17
(HPO:0000155) Oral ulcer 23441086 IBIS 9 / 7739
18
(HPO:0000271) Abnormality of the face Frequent [IBIS] 75 % (n=16) 23171239 IBIS 108 / 7739
19
(HPO:0000498) Blepharitis 23441086 IBIS 27 / 7739
20
(HPO:0000252) Microcephaly 20717171 IBIS 832 / 7739
21
(HPO:0001999) Abnormal facial shape 20717171 IBIS 169 / 7739
22
(HPO:0002007) Frontal bossing 25391451 IBIS 366 / 7739
23
(HPO:0000278) Retrognathia 25391451 IBIS 100 / 7739
24
(HPO:0000365) Hearing impairment 25391451 IBIS 539 / 7739
25
(HPO:0001328) Specific learning disability 20717171 IBIS 114 / 7739
26
(HPO:0001263) Global developmental delay 20717171 IBIS 853 / 7739
27
(HPO:0001249) Intellectual disability 22050868 IBIS 1089 / 7739
28
(HPO:0002557) Hypoplastic nipples 22050868 IBIS 33 / 7739
29
(HPO:0000823) Delayed puberty 25391451 IBIS 65 / 7739
30
(HPO:0000821) Hypothyroidism 25391451 IBIS 141 / 7739
31
(HPO:0000824) Growth hormone deficiency 20717171 IBIS 56 / 7739
32
(HPO:0008187) Absence of secondary sex characteristics 20717171 IBIS 5 / 7739
33
(HPO:0007598) Bilateral single transverse palmar creases 20717171 IBIS 13 / 7739
34
(HPO:0011304) Broad thumb 20717171 IBIS 39 / 7739
35
(HPO:0000768) Pectus carinatum 20717171 IBIS 136 / 7739
36
(HPO:0000954) Single transverse palmar crease 20717171 IBIS 162 / 7739
37
(HPO:0002240) Hepatomegaly 24796372 IBIS 467 / 7739
38
(HPO:0000023) Inguinal hernia 20717171 IBIS 181 / 7739
39
(HPO:0002037) Inflammation of the large intestine 25288127 IBIS 25 / 7739
40
(HPO:0001744) Splenomegaly 24796372 IBIS 337 / 7739
41
(HPO:0001508) Failure to thrive Frequent [IBIS] 43.8% (n=16) 22050868 IBIS 454 / 7739
42
(HPO:0001510) Growth delay 20717171 IBIS 295 / 7739
43
(HPO:0200042) Skin ulcer 20717171 IBIS 138 / 7739
44
(HPO:0007552) Abnormal subcutaneous fat tissue distribution 20717171 IBIS 12 / 7739
45
(HPO:0001015) Prominent superficial veins Frequent [IBIS] 87.5% (n=16) 22050868 IBIS 7 / 7739
46
(HPO:0000973) Cutis laxa Occasional [IBIS] 12.5 % (n=16) 22050868 IBIS 43 / 7739
47
(HPO:0001631) Atria septal defect Frequent [IBIS] 74.5% (n=51) 23171239 IBIS 274 / 7739
48
(HPO:0011648) Patent ductus arteriosus after birth at term 23056709 IBIS 18 / 7739
49
(HPO:0001684) Secundum atrial septal defect 19011569 IBIS 14 / 7739
50
(HPO:0001671) Abnormality of the cardiac septa 23171239 IBIS 55 / 7739
51
(HPO:0001643) Patent ductus arteriosus 23056709 IBIS 228 / 7739
52
(HPO:0004415) Pulmonary artery stenosis 23171239 IBIS 25 / 7739
53
(HPO:0001653) Mitral regurgitation 23171239 IBIS 64 / 7739
54
(HPO:0030680) Abnormality of cardiovascular system morphology 20717171 IBIS 355 / 7739
55
(HPO:0001642) Pulmonic stenosis 23171239 IBIS 89 / 7739
56
(HPO:0002092) Pulmonary hypertension 19011569 IBIS 109 / 7739
57
(HPO:0002619) Varicose veins 20717171 IBIS 11 / 7739
58
(HPO:0004311) Abnormality of macrophages 25288127 IBIS 7 / 7739
59
(HPO:0012133) Erythroid hypoplasia 20717171 IBIS 5 / 7739
60
(HPO:0001903) Anemia 19011569 IBIS 289 / 7739
61
(HPO:0001888) Lymphopenia 19011569 IBIS 43 / 7739
62
(HPO:0001875) Neutropenia 25288127 IBIS 83 / 7739
63
(HPO:0010974) Abnormality of myeloid leukocytes 25288127 IBIS 6 / 7739
64
(HPO:0010977) Abnormality of phagocytes 25288127 IBIS 4 / 7739
65
(HPO:0001874) Abnormality of neutrophils 20975743 IBIS 47 / 7739
66
(HPO:0001873) Thrombocytopenia Frequent [IBIS] 58% (n=50) 23171239 IBIS 224 / 7739
67
(HPO:0011993) Impaired neutrophil bactericidal activity 20616219 IBIS 3 / 7739
68
(HPO:0012311) Monocytosis 19011569 IBIS 10 / 7739
69
(HPO:0001882) Leukopenia 25288127 IBIS 51 / 7739
70
(HPO:0004854) Intermittent thrombocytopenia 25391451 IBIS 3 / 7739
71
(HPO:0003206) Decreased activity of NADPH oxidase 25288127 IBIS 8 / 7739
72
(HPO:0004363) Abnormality of calcium homeostasis 25288127 IBIS 4 / 7739
73
(HPO:0002093) Respiratory insufficiency 19011569 IBIS 410 / 7739
74
(HPO:0002205) Recurrent respiratory infections 20717171 IBIS 254 / 7739
75
(HPO:0011947) Respiratory tract infection 25391451 IBIS 28 / 7739
76
(HPO:0002719) Recurrent infections 19118303 IBIS 107 / 7739
77
(HPO:0002721) Immunodeficiency 20717171 IBIS 97 / 7739
78
(HPO:0002718) Recurrent bacterial infections 19118303 IBIS 75 / 7739
79
(HPO:0000778) Hypoplasia of the thymus 19011569 IBIS 13 / 7739
80
(HPO:0100806) Sepsis 23441086 IBIS 48 / 7739
81
(OMIM) Poor secondary sexual development (1 family) 20717171 IBIS 1 / 7739
82
(HPO:0040019) Finger clinodactyly 20717171 IBIS 1 / 7739
83
(OMIM) Dysplastic changes in all cell lineages in the bone marrow 20975743 IBIS 1 / 7739
84
(OMIM) Vacuolization in myeloid cell lines in the bone marrow 20616219 IBIS 1 / 7739
85
(OMIM) Few mature neutrophils in the bone marrow 20975743 IBIS 1 / 7739

Associated genes:

G6PC3;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Clinical Description OMIM Boztug et al. (2009) reported an extended consanguineous kindred from Aramean, Turkey, in which 4 children had a syndrome comprising severe congenital neutropenia, cardiac abnormalities, and a prominent superficial venous pattern. Three presented with neonatal sepsis, the fourth ...
Molecular genetics OMIM In affected members of a large consanguineous Turkish family and an unrelated Turkish child with SCN4, Boztug et al. (2009) identified a homozygous mutation in the G6PC3 gene (611045.0001). In vitro functional expression assays showed that patient neutrophils ...