Table 1.
Summary of clinical phenotypes in patients with previously reported SLC6A9 gene variants.
| SLC6A9 variants (NM_201649.4) | Pedigree and case number | Prenatal manifestations | Main manifestations after birth | Glycine concentration | Brain MRI | Reference |
|---|---|---|---|---|---|---|
| c.1219A > G (p.Ser407Gly) homozygosity, heterozygous parents, consanguineous marriage | Pedigree 1 case 1 | Polyhydramnios | Female, 15-month-old, full term birth, recurrent apneic episodes, respiratory distress after birth, hypotonia that rapidly transformed into hypertonicity with pronounced startle-like clonus jerks, cranial and facial dysmorphism, talipes equinovarus, global delay | Elevated normal serum glycine level (288 μmol/L)↑ | Bilateral subinsular white matter T2 hyperintensity, right head of caudate atrophy with tiny cyst, and bilateral scattered subcortical and periventricular white matter changes | (3) |
| Elevated CSF glycine level (21 μmol/L)↑ | ||||||
| c.928_932del (p.Lys310PhefsTer31) homozygosity, heterozygous parents, consanguineous marriage | Pedigree 2 case 2 | NT4.2 mm, fourth ventricle dilation, bilateral clubfeet, polyhydramnios | Female, 2-year-old, born at 33 weeks of gestation, recurrent apneic episodes, respiratory distress after birth, hypotonia that rapidly transformed into hypertonicity with pronounced startle-like clonus jerks, cranial and facial dysmorphism, arthrogryposis, talipes equinovarus, other limb or skeletal deformities, hypertension | Normal serum glycine level | Enlargement of lateral and third ventricles, mildly excessive extra-axial fluid, a focal area of restriction diffusion in the left hemisphere of the cerebellum | (12) |
| Elevated CSF glycine level (22 μmol/L) ↑ | ||||||
| Pedigree 2 case 3 | NT6.0 mm, hydrops (edema of the abdominal wall and scalp) | termination of pregnancy | NA | NA | ||
| c.1717C > T (p.Gln573*) homozygosity, heterozygous parents, consanguineous marriage | Pedigree 3 case 4 | NA | Female, born at 35 weeks of gestation, respiratory distress after birth, hypotonia that rapidly transformed into hypertonicity with pronounced startle-like clonus jerks, cranial and facial dysmorphism, arthrogryposis, other limb or skeletal deformities, death due to recurrent apnea episodes on the 18th day after birth | Elevated CSF glycine level ↑ | NA | |
| Pedigree 3 case 5 | Arthrogryposis | Female, born at 41 weeks of gestation, respiratory distress after birth, hypotonia that rapidly transformed into hypertonicity with pronounced startle-like clonus jerks, cranial and facial dysmorphism, arthrogryposis, other limb or skeletal deformities, death due to respiratory failure and bradycardia on the second day after birth | NA | NA | ||
| Pedigree 3 case 6 | Arthrogryposis, hyperextension of knees, bilateral club feet, no movement of feet or elbows, deviations of his fingers | Male, born at 30 weeks of gestation, respiratory distress after birth, hypotonia that rapidly transformed into hypertonicity with pronounced startle-like clonus jerks, cranial and facial dysmorphism, arthrogryposis, talipes equinovarus, other limb or skeletal deformities, cryptorchidism, inguinal hernia, atrial septal defect, hypotension, conductive hearing impairment, death due to respiratory failure on the 7th month after birth | Normal serum glycine level | Thin corpus callosum and bilateral optic nerve atrophy | ||
| elevated CSF glycine level (25–31 μmol/L) ↑ | ||||||
| c.352G > A (p.Val118Met) homozygosity, heterozygous parents, non-consanguineous marriage | Pedigree 4 case 7 | Increased NT, arthrogryposis | Termination of pregnancy | NA | NA | (13) |
| Pedigree 4 case 8 | Increased NT, arthrogryposis | Termination of pregnancy | NA | NA | ||
| c.997delC (p.Arg333Alafs*3) homozygosity, heterozygous parents, consanguineous marriage | Pedigree 5 case 9 | Polyhydramnios, cryptorchidism, bilateral clubfeet, lack of lower limb movements | Male, born at 38 weeks of gestation, respiratory distress after birth, hypotonia that rapidly transformed into hypertonicity with pronounced startle-like clonus jerks, cranial and facial dysmorphism, arthrogryposis, talipes equinovarus, other limb or skeletal deformities, scoliosis, micropenis, cryptorchidism, death due to respiratory failure on the 13th day after birth | Normal serum glycine level (234.9 μmol/L) | Normal | (14) |
| Elevated CSF glycine level (49.5 μmol/L) ↑ | ||||||
| Pedigree 5 case 10 | NT6.2 mm, bilateral clubfeet | natural miscarriage at 16 weeks | NA | NA | ||
| c.469G > A (p.Glu157Lys) homozygosity, heterozygous parents, consanguineous marriage | Pedigree 6 case 11 | NT2.5 mm, macrocephaly, polyhydramnios, hydrops, absent fetal movement | Male, born at 32 weeks of gestation of gestation, death due to bradycardia and hydrops within the first postnatal hour, cranial and facial dysmorphism, thoracic kyphosis, hypertrichosis, arthrogryposis, talipes equinovarus, other limb or skeletal deformities, hemosiderosis, lung hypoplasia | NA | NA | (15) |
| Pedigree 6 case 12 | Polyhydramnios, bilateral clubfeet, knee hypextension, hydrops | Female, born at 32 weeks of gestation, death due to hydrops within the first postnatal hour, cranial and facial dysmorphism, arthrogryposis, talipes equinovarus, other limb or skeletal deformities, hypertrichosis, short neck, thoracic kyphosis, atrial septal defect, hemosiderosis | NA | NA | ||
| Pedigree 6 case 13 | Bilateral clubfeet, bilateral flexion contractures of elbows, IUGR | Terminated at 16 weeks of gestation, due to absent fetal heart activity, cord hyper coiling, hemosiderosis | NA | NA | ||
| c.454C > T (p.Pro152Ser) homozygosity, heterozygous parents, consanguineous marriage | Pedigree 7 case 14 | NA | Female, born at term, poor sensorium after birth, hypotonia, seizures, death due to catecholamineresistant shock and cardiorespiratory failure at 72 h of life | Normal serum glycine level (519 μmol/L) | Mild cerebral edema | (16) |
| Elevated CSF glycine level (62.61 μmol/L) ↑ | ||||||
| c.859C > T(p.Arg287Trp), c.1120T > C(p.Cys374Arg) heterozygous parents, non-consanguineous marriage | Pedigree 8 case 15 | Bilateral clubfeet, bilateral choroid plexus cysts | Female, born at 39 weeks of gestation, dyspnea and recurrent apnea after birth, hypotonia that rapidly transformed into hypertonicity, cranial and facial dysmorphism, arthrogryposis, talipes equinovarus, other limb or skeletal deformities, necrotizing enterocolitis, pneumonia, anemia, death due to respiratory failure on the 4th day after birth | Normal serum glycine level (699.00 μmol/L) | NA | This case |
IUGR, intrauterine growth retardation; NT, nuchal translucency; MRI, magnetic resonance image; CSF, cerebrospinal fluid; NA, not available.