CaseFZ2: Male, Finland, 2.9 yrs deceased

CasePresentingHPOs: HP:0001511, HP:0008897, HP:0001999, HP:0000973, HP:0100678, HP:0000963, HP:0010648, HP:0001388, HP:0100790, HP:0001374, HP:0001181, HP:0001762, HP:0002650, HP:0000938, HP:0000270, HP:0002645, HP:0012443, HP:0025356, HP:0008872, HP:0001252, HP:0001348, HP:0000518, HP:0002677, HP:0000325, HP:0011220, HP:0000337, HP:0000411, HP:0000369 (Intrauterine growth retardation, Postnatal growth retardation, Abnormal facial shape, Cutis laxa, Premature skin wrinkling, Thin skin, Dermal translucency, Joint laxity, Hernia, Congenital hip dislocation, Adducted thumb, Talipes equinovarus, Scoliosis, Osteopenia, Delayed cranial suture closure, Wormian bones, Abnormality of brain morphology, Psychomotor retardation, Feeding difficulties in infancy, Muscular hypotonia, Brisk reflexes, Cataract, Small foramen magnum, Triangular face, Prominent forehead, Broad forehead, Protruding ear, Low-set ears)

HPOsFreeText: Typical facial gestalt, Reduced collagen type 1 and 3 production

CaseNotHPOs: HP:0000252, HP:0005116, HP:0000486 (Microcephaly, Arterial tortuosity, Strabismus)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo in this and two other cases with the same variant and similar presentation, No family history,

CasePreviousTesting: N/A

CaseGenotypingMethod: ALDH18A1 and PYRC1 were investigated by Sanger sequencing, with the latter revealing no abnormalities and the former showing a heterozygous change at the Arg138 residue. qPCR was used to exclude the presence of a exonic deletion and investigation revealed no further variants in the coding regions. Familial sequencing revealed the inheritance was de novo with no variants in the parents.

Variant: NM_002860.4(ALDH18A1):c.412C>T (p.Arg138Trp)

ClinVar: 217259 https://www.ncbi.nlm.nih.gov/clinvar/variation/217259/

gnomAD: Not in gnomAD

CaseFZ5: Male, Mexico, 4 yrs report

CasePresentingHPOs: HP:0001511, HP:0008897, HP:0001999, HP:0000973, HP:0100678, HP:0000963, HP:0010648, HP:0001388, HP:0001374, HP:0001181, HP:0001762, HP:0002650, HP:0000938, HP:0000270, HP:0025356, HP:0001252, HP:0001348, HP:0000518, HP:0000325, HP:0011220, HP:0000337, HP:0000411, HP:0000369, HP:0000252 (Intrauterine growth retardation, Postnatal growth retardation, Abnormal facial shape, Cutis laxa, Premature skin wrinkling, Thin skin, Dermal translucency, Joint laxity, Congenital hip dislocation, Adducted thumb, Talipes equinovarus, Scoliosis, Osteopenia, Delayed cranial suture closure, Psychomotor retardation, Muscular hypotonia, Brisk reflexes, Cataract, Triangular face, Prominent forehead, Broad forehead, Protruding ear, Low-set ears, Microcephaly)

HPOsFreeText: Typical facial gestalt

CaseNotHPOs: HP:0005116, HP:0000486, HP:0100790, HP:0002645, HP:0012443 (Arterial tortuosity, Strabismus, Hernias, Wormian bones, Abnormality of brain morphology)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo in this case with one other maternally-confirmed case with the same variant and similar presentation, No family history

CasePreviousTesting: N/A

CaseGenotypingMethod: ALDH18A1 and PYRC1 were investigated by Sanger sequencing, with the latter revealing no abnormalities and the former showing a heterozygous change at the Arg138 residue. qPCR was used to exclude the presence of a exonic deletion and investigation revealed no further variants in the coding regions. Familial sequencing revealed the inheritance was de novo with no variants in the parents.

Variant: NM_002860.4(ALDH18A1):c.413G>T (p.Arg138Leu)

ClinVar: 217261 https://www.ncbi.nlm.nih.gov/clinvar/variation/217261/

gnomAD: Not in gnomAD

CaseSK: Male, Pakistan, Birth onset

CasePresentingHPOs: HP:0008846, HP:0001562, HP:0002987, HP:0012453, HP:0001623, HP:0001518, HP:0003561, HP:0002209, HP:0011359, HP:0000963, HP:0100678, HP:0000973, HP:0100679, HP:0000348, HP:0002007, HP:0005280, HP:0000463, HP:0003196, HP:0000430, HP:0000233, HP:0000490, HP:0007759, HP:0000218, HP:0000347, HP:0005328, HP:0002828, HP:0002098, HP:0009110, HP:0000883, HP:0011682, HP:0001655, HP:0100545, HP:0007727, HP:0002033, HP:0002015, HP:0001250, HP:0000023, HP:0001525 (Severe intrauterine growth retardation, Oligohydramnios, Elbow contracture, Bilateral wrist flexion contracture, Breech presentation, Small for gestational age, Birth length less than 3rd percentile, Sparse scalp hair, Dry hair, Thin skin, Wrinkled skin, Cutis laxa, Lack of skin elasticity, High forehead, Frontal bossing, Depressed nasal bridge, Anteverted nares, Short nose, Underdeveloped nasal alae, Thin vermilion border, Deeply set eye, Opacification of the corneal stroma, High-arched palate, Micrognathia, Progeroid facial appearance, Multiple joint contractures, Respiratory distress, Diaphragmatic eventration, Thin ribs, Perimembranous ventricular septal defect, Patent foramen ovale, Arterial stenosis, Opacification of the corneal epithelium, Poor suck, Dysphagia, Seizures, Inguinal hernia, Severe failure to thrive)

HPOsFreeText: Clenched fists, Birth weight was 1.52 kg (<3rd centile), his length was 38 cm (<3rd centile) and his OFC was 29.5 cm (<3rd centile). His Apgar scores were six and nine at 1 and 5 min respectively, Parchment paper‐like textured skin, Prominent cheek jowls, Absent Bowman's membrane, Increased cellularity in the substantia propia, Decreased amount of elastin compared to controls, Less-deefined collagen fibers, Amounts of collagen type I and III were qualitatively decreased

CaseNotHPOs: N/A

NotHPOsFreeText: Normal lung parenchyma

CaseAddInfo: Born to consanguineous first-cousin once removed parents

CasePreviousTesting: Maternal TORCH analysis showed no signs of an acute infection; Amniocentesis showed a normal male karyotype (46,XY), and amniotic fluid virology studies showed no detectable virus; Fetal echocardiography was normal; Fibroblast analysis showed cell proliferation was severely diminished along with abnormally decreased collagen production; A heterozygous variant in PYCR1 was also found (c.329C > T) but is predicted benign and no functional expression alteration of PYCR1 was found.

CaseGenotypingMethod: The exons and exon-intron boundaries of ALDH18A1 were subject to mutation screening via direct sequencing and PCR amplification. A homozygous canonical splice-site variant was found with both parents heterozygous for the same mutation. cDNA was applied to test for functional alteration of the transcript which yielded, rathert than the WT 706 bp protein, a shortened protein ranging from 492-583 bp. These two transcripts either lead to a large deletion of c.1757–1970 or a premature termination codon predicted to undergo NMD.

Variant: NM_002860.4(ALDH18A1):c.1923+1G>A

ClinVar: 29727 https://www.ncbi.nlm.nih.gov/clinvar/variation/29727/

gnomAD: Not in gnomAD

Case25014: Female, 31 yrs onset, United States

CasePresentingHPOs: HP:0002527, HP:0002064, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0000012, HP:0006938, HP:0100658, HP:0000518, HP:0002322, HP:0010784, HP:0012104, HP:0006913 (Falls, Spastic gait, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Urinary urgency, Impaired vibration sensation at ankles, Cellulitis, Cataract, Resting tremor, Uterine neoplasm, Parietal cortical atrophy, Frontal cortical atrophy)

HPOsFreeText: 5/7 disability score, Chronic microvascular disease

CaseNotHPOs: HP:0001317, HP:0002464, HP:0100543, HP:0000973 (Abnormal cerebellum morphology, Spastic dysarthria, Cognitive impairment, Cutis laxa)

NotHPOsFreeText: N/A

CaseGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

CasePreviousTesting: N/A

CaseAddInfo: Case is sporadic

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

FamilyFSP856: France

FamilyPresentingHPOs: HP:0001263, HP:0002317, HP:0001324, HP:0007350, HP:0003487, HP:0006938, HP:0002066, HP:0002174, HP:0000252, HP:0001999 (Global developmental delay, Spastic gait, Muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Impaired vibration sensation at ankles, Gait ataxia, Postural tremor, Microcephaly, Abnormal facial shape)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0001260, HP:0000973 (Dysarthria, Cutis laxa)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

FamilyPreviousTesting: Normal MRI

FamilyAddInfo: Family displays autosomal recessive inheritance, Family is homozygous for this variant

Variant: NM_002860.4(ALDH18A1):c.2143G>C (p.Asp715His)

ClinVar: 217115 https://www.ncbi.nlm.nih.gov/clinvar/variation/217115/

gnomAD: 0.00002641, https://gnomad.broadinstitute.org/variant/10-97370017-C-G

Affected: 2

Unaffected: 2

Segregations: 4

AddSegregationInfo: Whole Exome Sequencing, Figure 1 Pedigree

FamilyFSP429: France

FamilyPresentingHPOs: HP:0002064, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0031993, HP:0003572, HP:0005961 (Spastic gait, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Hoffman sign, Low plasma citrulline, Hypoargininemia)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0000973, HP:0001999, HP:0100543 (Cutis laxa, Abnormal facial shape, Cognitive impairment)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

FamilyPreviousTesting: Amino acid levels in Table 4

FamilyAddInfo: Family displays autosomal dominant inheritance

Variant: NM_002860.4(ALDH18A1):c.1994G>T (p.Arg665Leu)

ClinVar: 217119 https://www.ncbi.nlm.nih.gov/clinvar/variation/217119/

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 7

Segregations: 1

AddSegregationInfo: Candidate gene sequencing, Figure 1 Pedigree

CaseGSHSP44: Female, 44 yrs onset, Australia/UK

CasePresentingHPOs: HP:0040083, HP:0002317, HP:0002064, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0000012, HP:0012104, HP:0006913, HP:0001761, HP:0031520, HP:0006827 (Toe walking, Unsteady gait, Spastic gait, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Urinary urgency, Parietal cortical atrophy, Frontal cortical atrophy, Pes cavus, Groin pain, Atrophy of the spinal cord)

HPOsFreeText: 4/7 disability score, Hip replacement

CaseNotHPOs: HP:0001317, HP:0002464, HP:0100543, HP:0000973, HP:0006938 (Abnormal cerebellum morphology, Spastic dysarthria, Cognitive impairment, Cutis laxa, Impaired vibration sensation at ankles)

NotHPOsFreeText: N/A

CaseGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

CasePreviousTesting: N/A

CaseAddInfo: Case is sporadic

Variant reported as c.1949G>T which does not exist in current transcripts

Variant: NM_002860.3:c.1955C>T (p.Ser652Phe)

CAID: CA377700120 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377700120

gnomAD: Not in gnomAD

CaseGSHSP44: Female, 44 yrs onset, Australia/UK

CasePresentingHPOs: HP:0040083, HP:0002317, HP:0002064, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0000012, HP:0012104, HP:0006913, HP:0001761, HP:0031520, HP:0006827 (Toe walking, Unsteady gait, Spastic gait, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Urinary urgency, Parietal cortical atrophy, Frontal cortical atrophy, Pes cavus, Groin pain, Atrophy of the spinal cord)

HPOsFreeText: 4/7 disability score, Hip replacement

CaseNotHPOs: HP:0001317, HP:0002464, HP:0100543, HP:0000973, HP:0006938 (Abnormal cerebellum morphology, Spastic dysarthria, Cognitive impairment, Cutis laxa, Impaired vibration sensation at ankles)

NotHPOsFreeText: N/A

CaseGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

CasePreviousTesting: N/A

CaseAddInfo: Case is sporadic

Variant reported as c.1949G>T which does not exist in current transcripts

Variant: NM_002860.3:c.1955C>T (p.Ser652Phe)

CAID: CA377700120 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377700120

gnomAD: Not in gnomAD

FamilyPA1: United Kingdom

FamilyPresentingHPOs: HP:0000518, HP:0002493, HP:0004322, HP:0001263, HP:0011842, HP:0002013 (Cataract, Upper motor neuron dysfunction, Short stature, Global developmental delay, Abnormality of skeletal morphology, Vomiting)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: ALDH18A1 was directly sequenced upon investigation for a causal role in SPG9, due to being within the linked region 10q23.3-q24.2, not having been discarded as a candidate gene, and mutations having been known to cause cutis laxa. This revealed one mutation in each pedigree that strictly co-segregated with the disease. Exome NGS sequencing within the interval showed only two variants were unknown in ExAC with the MYOF substitution unlikely to be disease causing due to poor conservation.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family shows autosomal dominant segregation

FamilyPMIDs: 8779323

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

Affected: 7

Unaffected: 3

Segregations: 6

AddSegregationInfo: Candidate Gene Sequencing, Pedigree in Family 1

FamilyPA1: United Kingdom

FamilyPresentingHPOs: HP:0000518, HP:0002493, HP:0004322, HP:0001263, HP:0011842, HP:0002013 (Cataract, Upper motor neuron dysfunction, Short stature, Global developmental delay, Abnormality of skeletal morphology, Vomiting)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: ALDH18A1 was directly sequenced upon investigation for a causal role in SPG9, due to being within the linked region 10q23.3-q24.2, not having been discarded as a candidate gene, and mutations having been known to cause cutis laxa. This revealed one mutation in each pedigree that strictly co-segregated with the disease. Exome NGS sequencing within the interval showed only two variants were unknown in ExAC with the MYOF substitution unlikely to be disease causing due to poor conservation.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family shows autosomal dominant segregation

FamilyPMIDs: 8779323

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

Affected: 7

Unaffected: 3

Segregations: 6

AddSegregationInfo: Candidate Gene Sequencing, Pedigree in Family 1