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Use of expanded carrier screening for retrospective diagnosis of two deceased siblings with Van Maldergem syndrome 2: case report

Nasim Rahmani
Nasim Rahmani
, 
Mohammad Ahmadvand
Mohammad Ahmadvand
 e 
Golnaz Khakpour
Golnaz Khakpour
   | 01 ago 2023
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INFORMAZIONI SU QUESTO ARTICOLO
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Article Category: Clinical vignettes
Pubblicato online: 01 ago 2023
Pagine: 322 - 328
DOI: https://doi.org/10.2478/abm-2022-0036
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© 2023 Nasim Rahmani et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1.

Pedigree of the patients. Proband 1 (V:1) was born from consanguineous first cousins once removed parents (III:1 and IV:1) and was affected by MCA resembling VMS. His sibling, proband 2, (V:2) had a similar phenotype. Both deceased in the second month of life. Circle, female; Square, male; VMS, Van Maldergem syndrome.
Pedigree of the patients. Proband 1 (V:1) was born from consanguineous first cousins once removed parents (III:1 and IV:1) and was affected by MCA resembling VMS. His sibling, proband 2, (V:2) had a similar phenotype. Both deceased in the second month of life. Circle, female; Square, male; VMS, Van Maldergem syndrome.

Figure 2.

Possible consequence of the variant c.7018+1G>A, NM_024582.6, on the transcript. (A) Normal splicing, using 5’ CSS, joins exon 6 to 7 and (B) the junction forms Glycine codon (GGA). (C) This variant can result in the loss of 5′ CSS and aberrant splicing. Theoretically, insertion of the fragment from intron 6 in the transcript creates the codon of Aspartic acid in junction and leads to frameshift creating a premature stop codon, UAA, in position +33 to +35.CSS, canonical splice site; nts, nucleotides,
Possible consequence of the variant c.7018+1G>A, NM_024582.6, on the transcript. (A) Normal splicing, using 5’ CSS, joins exon 6 to 7 and (B) the junction forms Glycine codon (GGA). (C) This variant can result in the loss of 5′ CSS and aberrant splicing. Theoretically, insertion of the fragment from intron 6 in the transcript creates the codon of Aspartic acid in junction and leads to frameshift creating a premature stop codon, UAA, in position +33 to +35.CSS, canonical splice site; nts, nucleotides,

Comparison of normal CSS, GT, in the intron 6 of FAT4 and its mutant, AT, by in silico splice prediction tools and two predicted cryptic donor sites

Sequences exon/intron Position in intron 6 NNSPLICE NetGene2 SD-score
Normal CSS GATTCAG/GTAAGTCC +1 1.00 1–0.83 −2.074
Mutant CSS GATTCAG/ATAAGTCC +1 - - -
Predicted donor sites CATGGTG/GTGCGTGC +191 0.74 0–0.41 −3.998
GACATGG/GTGAGTGA +683 0.99 1–0.00 −2.277

Table shows variants detected in three genes that parents are heterozygous carriers for them. They share common variants in PINK1 and PTPRQ genes, but they are carriers for different variants in MYO15A gene

Gene/transcript Variant Loc. Chr. pos. Related phenotypes OMIM number Inh. Class†
The couple both are heterozygous carriers for the same variants in PINK1 and PTPRQ genes
PINK1 NM_032409 c.709A>G p.M237V Exon 3 Chr1: 20966418 Early onset Parkinson disease 6 605909 AR VUS
PTPRQ‡ NM_001145026 c.3446-5 dupT Intron 21 Chr12: 80542081 Autosomal recessive deafness 84A 613391 AR Benign
Autosomal dominant deafness-73 617663 AD
The couple are heterozygous carriers for different variants in MYO15A gene
MYO15A NM_016239 c.3622C>T p.R1208C Exon 3 Chr17: 18027809 Autosomal recessive deafness-3 600316 AR VUS
c.5230T>A P.S1744T Exon 20 Chr17: 18043849 VUS

Phenotypic comparison of P1 and P2 with HKLLS and VMLDS characteristics previously described in the literature [1, 4, 5, 24]

Abnormalities HS VMS P1 P2
Microcephaly + ++ No No
Large fontanelle − +++ No No
Blepharo-nasal malformation +++ +++ Yes Yes
Micrognathia and small mouth +++ +++ Yes Yes
Irregular dentition +++ +++ NA NA
Short stature +++ +++ NA NA
Hypertelorism +++ +++ No No
Epicanthic folds +++ +++ Yes Yes
Camptodactyly ++ +++ No Yes
Syndactyly + + No No
Clubfoot + + Yes No
Microtia +++ +++ Yes Yes
Conductive hearing loss +* +++ Yes Yes
Cardiac malformation +* + No Yes
Infantile hypotonia +* +++ No No
Developmental delay +++ +++ NA NA
Feeding difficulties + +++ Yes Yes
Choanal atresia/stenosis − ++ No No
Tracheal anomalies − +++ Yes Yes
Periventricular nodular heterotopia − ++ Not performed
Corpus callosum anomalies − ++ Not performed
Other brain anomalies +* +
Renal anomalies − +++ No Yes
Genital anomalies edema + No No
Lymphedema limb +++ +* No No
Primary intestinal lymphangiectasia +++ −* No No
Other lymphangiectasia ++ − No No
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